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PeptideAI
Human RCTcardiovascular

Serelaxin

Recombinant human relaxin, the pregnancy hormone that widens blood vessels and boosts renal blood flow, trialled as a 48-hour infusion in acute heart failure and ultimately unsuccessful.

Also known as recombinant human relaxin-2, RLX030, rhRlx, Reasanz, RLX030, RLX-030

Human RCT — Randomised controlled trials in humans, but not an approved product for this use.

RELAX-AHF in 2013 was positive on dyspnoea relief and showed an unexpected 37 percent reduction in 180-day mortality, which generated enormous excitement. The confirmatory 6,600-patient RELAX-AHF-2 trial in 2019 flatly failed to reproduce either the cardiovascular death or the worsening-heart-failure benefit. The FDA and EMA both declined approval. This is a textbook case of a striking secondary finding that did not survive replication.

How it works

Relaxin-2 is the peptide that lets the maternal circulation accommodate pregnancy: cardiac output rises, systemic and renal vascular resistance fall, and glomerular filtration climbs by roughly half. Serelaxin is the recombinant form, a two-chain insulin-superfamily peptide linked by disulfide bridges. It signals through the G-protein-coupled RXFP1 receptor, raising cAMP and activating endothelial nitric oxide synthase and the endothelin type B receptor pathway, producing a slow-onset, sustained vasodilatation that is more renal-sparing than nitrate-based vasodilators. It also has antifibrotic and anti-inflammatory activity through TGF-beta and matrix metalloproteinase modulation, which is why it drew interest in scleroderma and portal hypertension as well as heart failure.

Targets: RXFP1 (relaxin family peptide receptor 1), Endothelial nitric oxide synthase, Endothelin type B receptor, TGF-beta signalling

Dosing

ProtocolDoseFrequencyRoute
Acute heart failure - RELAX-AHF trial protocolStarted within 16 hours of hospital presentation with acute heart failure.—single continuous 48-hour infusionintravenous
  • · 30 mcg/kg/day by continuous IV infusion for 48 hours. Weight-based, so no fixed microgram dose applies. Infusion rate was halved or stopped if systolic blood pressure dropped more than 40 mmHg from baseline or below 100 mmHg.

Titration

Not titrated for efficacy - only reduced or stopped for hypotension. The fixed 30 mcg/kg/day rate was carried from phase 2 into both phase 3 trials.

Cycling

Studied only as a single 48-hour infusion at the time of an acute decompensation. There is no chronic dosing paradigm.

Work out your exact syringe units →

Pharmacology

Half-life
Terminal half-life in the region of several hours; the clinical effect is defined by the continuous 48-hour infusion rather than by bolus kinetics.
Onset
Dyspnoea relief and blood pressure reduction began within the first 6-24 hours of infusion in the RELAX-AHF trials.
Routes
intravenous
Molecule
Recombinant two-chain human relaxin-2 peptide hormone
Sequence length
53 amino acids
Molecular weight
5963 Da

Handling

Diluent
Investigational preparation used sterile diluent and dextrose for infusion
Lyophilised
Investigational material was stored refrigerated.
Reconstituted
Diluted infusion was prepared fresh for each 24-hour period in the trials.
Light sensitive
Yes — keep it out of the light

Mixing

Never commercialised, so there is no marketed reconstitution standard.

Side effects

  • commonHypotension— The predictable consequence of systemic vasodilatation and the main reason for rate reduction in the trials.
  • commonHeadache
  • commonAnaemia and mild haemodilution
  • commonBack pain
  • uncommonElevated liver enzymes

Do not use if

  • Systolic blood pressure below 125 mmHg, which was the trial entry floor - serelaxin lowers pressure further.
  • Cardiogenic shock or preload-dependent circulation.
  • Any use outside a clinical trial, since the drug was never approved and is not manufactured for sale.

Combining it

  • cautionnitrates — Additive vasodilatation and hypotension.
  • cautionACE inhibitors — Additive blood pressure lowering during the infusion.
  • redundantnesiritide — Both are vasodilatory infusions for the same acute heart failure indication, and both failed on outcomes.

What to monitor

  • · Continuous or frequent blood pressure measurement throughout the 48-hour infusion.
  • · Serum creatinine and electrolytes daily.
  • · Liver enzymes.
  • · Dyspnoea score, which was the endpoint the drug moved in RELAX-AHF.

Legal status

Not approved anywhere. Development for acute heart failure was discontinued after RELAX-AHF-2; no commercial product exists.

References

  • Teerlink et al. 2013, RELAX-AHF, serelaxin in acute heart failure, Lancet (trial)
  • Metra et al. 2019, RELAX-AHF-2, effects of serelaxin in patients with acute heart failure, NEJM (trial)

Mechanism in depth

Relaxin-2 is the hormone that reconfigures the maternal circulation in pregnancy: within weeks of conception it drops systemic vascular resistance by around 30 percent, raises cardiac output, and increases renal blood flow and glomerular filtration by 40 to 60 percent, all without the compensatory neurohormonal activation that a drug-induced vasodilation would trigger. That is an extraordinarily attractive profile for acute heart failure, and it is exactly why serelaxin was developed. It acts on RXFP1, a leucine-rich repeat G protein-coupled receptor, coupling through Gs to raise cAMP and through downstream nitric oxide, endothelin type B receptor and vascular endothelial growth factor pathways. It also upregulates matrix metalloproteinases and suppresses TGF-beta-driven collagen deposition, which gives it genuine antifibrotic activity, and it increases arterial compliance rather than simply dilating resistance vessels. RELAX-AHF, in 1,161 patients, showed the dyspnoea benefit it was designed to show and then, as a secondary finding, a 37 percent reduction in 180-day mortality that nobody had predicted and everybody wanted to believe. The confirmatory trial, RELAX-AHF-2, enrolled 6,545 patients and found 180-day cardiovascular death rates of 8.7 percent on serelaxin and 8.9 percent on placebo. That is not a near-miss; it is a flat line. Both the FDA and EMA declined approval. The mechanism is real, the biology is real, and the outcome benefit was noise.

What usually goes wrong

What went wrong with serelaxin is a lesson rather than a side effect. A 37 percent reduction in 180-day mortality in a 1,161-patient trial, appearing as a secondary endpoint in a study whose primary endpoints were about breathlessness, was always more likely to be a chance finding than a real effect, and a confirmatory trial six times the size found nothing at all. The intermediate biomarkers moved in the right direction in both trials. That is the trap: creatinine, cystatin C, troponin and NT-proBNP all improving does not mean patients live longer. Clinically, the practical risk during use was hypotension, which is unsurprising for a potent vasodilator infused for 48 hours. It was never approved anywhere and is not available.

Bloodwork worth running

MarkerWhenWhy it matters
Serum creatinine and cystatin CBaseline, day 2, day 5 and day 14.One of the most consistent findings across the RELAX-AHF programme was less worsening renal function on serelaxin, measured on both creatinine and cystatin C. This was the biomarker signal that made people believe the mortality result.Act if: A creatinine rise despite serelaxin suggests the congestion is not being relieved and the diuretic strategy needs revisiting.
NT-proBNPBaseline, day 2 and day 5.Fell faster on serelaxin in the biomarker substudies, consistent with faster decongestion. Unlike BNP, it is not confounded by any of these peptide drugs.Act if: A failure to fall by 30 percent by day 5 is a poor prognostic sign regardless of drug.
High-sensitivity troponinBaseline, day 2 and day 5.Serelaxin reduced troponin release in the biomarker programme, interpreted as less myocardial injury during the decompensation episode.
Liver transaminasesBaseline and day 5.The RELAX-AHF biomarker programme included hepatic markers because congestive hepatopathy tracks right-sided congestion, and serelaxin improved them.
Systolic blood pressureContinuously during the 48-hour infusion.The trials required a systolic above 125 mmHg at entry precisely because this is a potent vasodilator. Outside that population the safety is unknown.Act if: A fall below 100 mmHg, or a drop of more than 40 mmHg from baseline, means reduce or stop the infusion.

Pharmacokinetics

Bioavailability
100%
Time to steady state
0.2 days
Crosses blood-brain barrier
no
Metabolism
Proteolytic degradation of the two-chain insulin-superfamily structure.
Elimination
Not characterised in published sources at a level I can state.

Receptor targets

  • RXFP1 (relaxin family peptide receptor 1)

    Gs-coupled cAMP elevation, nitric oxide generation, VEGF and matrix metalloproteinase upregulation, TGF-beta suppression. Produces systemic and renal vasodilation, increased arterial compliance, and antifibrotic signalling.

  • Endothelin type B receptor (indirect)

    Part of the downstream vasodilatory cascade; relaxin signalling increases ETB-mediated nitric oxide release rather than binding the receptor directly.

Trials

  • RELAX-AHF Phase 3 · n=1161 · 26 weeks · 2013

    Two dyspnoea endpoints: the visual analogue scale area under the curve to day 5, which serelaxin improved (448 mm.h, p=0.007), and a Likert scale measure, which it did not (p=0.70). Cardiovascular death or heart failure readmission at 60 days was unchanged. The 180-day all-cause mortality reduction was a secondary finding.

  • RELAX-AHF-2 Phase 3 · n=6545 · 26 weeks · 2019

    Co-primary endpoints of cardiovascular death at 180 days and worsening heart failure at day 5. Cardiovascular death occurred in 8.7 percent on serelaxin and 8.9 percent on placebo. Neither endpoint was met. The trial that ended the drug.

What to expect, and when

Haemodynamic effects appear within the first hours of the infusion, with dyspnoea separation from placebo detectable by day 1 and maximal over the 5-day assessment window. The infusion is fixed at 48 hours, and the biomarker effects on creatinine and troponin were measured over days 2 to 14. There is no chronic dosing experience.

Stacking and comparisons

Serelaxin was given on top of standard acute heart failure care, which means loop diuretics and often nitrates, and it is additively hypotensive with all of it. The entry criterion of systolic blood pressure above 125 mmHg was not incidental; the drug was never tested in the hypotensive patients who make up a large share of real decompensations. Concurrent ACE inhibitors, ARBs, sacubitril/valsartan and PDE5 inhibitors all compound the vasodilation. Nothing about the stacking is complicated, because there is no reason for anyone to be taking it.

Against nitroglycerin and nesiritide, the other vasodilators tried in acute heart failure: serelaxin had the most attractive mechanism of the three, with renal blood flow preservation and antifibrotic signalling on top of vasodilation, and it failed the same way they did. The pattern across this entire class is now unmistakable, which is why the field has moved to early guideline-directed therapy initiation and decongestion strategies rather than searching for a better acute vasodilator. Longer-acting RXFP1 agonists such as LY3540378 and R2R01 are in development on the theory that 48 hours was simply not enough exposure; that hypothesis has not been tested at scale.

Rough cost

Never approved and never marketed; no price exists.

Genuinely uncertain

  • Volume of distribution, clearance, protein binding and terminal half-life for serelaxin are not published in sources I could resolve; the Core record itself declines to give a half-life.
  • The 37 percent 180-day mortality reduction in RELAX-AHF is quoted from the widely reported secondary analysis; the abstract I verified reports fewer deaths at day 180 without my having confirmed that exact percentage.
  • Whether longer or repeated relaxin exposure would produce an outcome benefit is an open question that the failed 48-hour trials do not answer.

Papers