🧬 Aging Wiki

anakinra

Properties1
aliasesKineret, rIL-1Ra, recombinant IL-1 receptor antagonist, Antril

11 min read

Partially verified 2026-05-07 (claude). Larsen 2007 NEJM PDF read end-to-end; corrections applied (per-arm n, p-value precision, injection-site reaction rate, PK half-life). ChEMBL identity confirmed. ClinicalTrials.gov count updated to 29 (all active trials; 3 most aging-relevant noted in table). Bresnihan 1998, Brucato 2016, Abbate 2022, Ridker 2016, Salmon 2022 PDFs not available — those claims unverified against full text. See verified-scope in frontmatter.

Anakinra

A recombinant, non-glycosylated form of the endogenous human interleukin-1 receptor antagonist (IL-1Ra) that competitively occupies IL-1 receptor type I (IL-1R1) without triggering receptor signalling, thereby blocking both IL-1α and IL-1β from engaging their shared receptor. Marketed by Swedish Orphan Biovitrum (SOBI) as Kineret; FDA-approved since 2001 for rheumatoid arthritis, and subsequently for rare autoinflammatory monogenic syndromes, systemic juvenile idiopathic arthritis (sJIA), and recurrent pericarditis. Anakinra is the wiki’s closest clinical analog to canakinumab for the chronic-inflammation hallmark, with a critical mechanistic distinction: anakinra blocks both IL-1 isoforms at the receptor, whereas canakinumab neutralises IL-1β only.

PubChem CID: null — biologics (recombinant proteins) are not assigned small-molecule PubChem CIDs; the frontmatter field is inapplicable for recombinant protein therapeutics. needs-canonical-id — verify whether a PubChem biological sequences entry or cross-reference exists for anakinra.

Identity

  • Class: recombinant protein therapeutic; N-terminally methionylated, non-glycosylated analogue of human IL-1Ra
  • Length: 153 amino acids (native IL-1Ra) + N-terminal Met = 154 aa; ChEMBL lists 166 aa including the signal peptide precursor form
  • Molecular weight: ~17.3 kDa (17,300 Da); consistent with the 153-residue non-glycosylated form
  • Molecular formula: C759H1186N208O232S10 (to be verified against primary characterisation source)
  • Trade name: Kineret (SOBI); formerly also Antril
  • ChEMBL ID: CHEMBL1201570 (confirmed: preferred name “ANAKINRA”, molecule type “Protein”, first approved 2001)
  • DrugBank ID: DB00026
  • WHO INN: anakinra

Target and mechanism

Anakinra is a competitive antagonist at IL-1R1 and IL-1R type II (IL-1R2). It binds both receptor subtypes without recruiting the IL-1 receptor accessory protein (IL-1RAcP) and therefore cannot initiate the downstream MyD88–IRAK–TRAF6–IKK–NF-κB signalling cascade that IL-1α or IL-1β would trigger. The mechanistic consequence is complete blockade of both IL-1 isoform signals at therapeutic concentrations.

This receptor-level mechanism distinguishes anakinra from:

  • canakinumab — binds free IL-1β only; leaves IL-1α-mediated signalling intact. CANTOS-type benefit is therefore IL-1β-selective. Anakinra, by blocking both isoforms, should in principle suppress a broader swathe of the inflammatory programme — including IL-1α-driven components of the SASP (IL-1α is a paracrine SASP amplifier and can drive senescence spreading). Whether this broader blockade translates to additive benefit vs higher infection risk is unresolved. needs-replication
  • rilonacept — IL-1 trap (decoy receptor fusion protein) capturing both IL-1α and IL-1β extracellularly; longer half-life than anakinra.
  • canakinumab — see above.

The upstream pathway context: nlrp3-inflammasome → IL-1β cleavage → IL-1R1 engagement → nf-kb → pro-inflammatory gene expression. Anakinra blocks the receptor step; canakinumab blocks the cytokine step. See chronic-inflammation for the full inflammaging network.

Pharmacokinetics

ParameterValue
RouteSubcutaneous injection (SC)
Standard dose100 mg/day SC (RA and most autoinflammatory indications)
NOMID/CAPSUp to 2–8 mg/kg/day may be required
Half-life~6–8 hours (short, due to renal clearance of the small ~17 kDa protein) [Larsen 2007 discussion; package insert range]
Bioavailability (SC)~95%
ClearancePredominantly renal filtration (small molecular weight bypasses FcRn recycling unlike IgG antibodies)
Tmax3–7 hours post-SC injection

The short ~6–8 hour half-life requires daily subcutaneous dosing — a significant practical burden relative to canakinumab’s once-every-3-months schedule. This contributes to adherence challenges outside specialised clinic settings and limits large-scale prevention use.

FDA approvals

YearIndication
2001Rheumatoid arthritis (moderately-to-severely active; 18+) — first biologic approval for RA 1
2012Neonatal-onset multisystem inflammatory disease (NOMID) / CAPS
2020Systemic juvenile idiopathic arthritis (sJIA) — FDA-approved in paediatric patients ≥2 yr
2021Recurrent pericarditis (colchicine-resistant / corticosteroid-dependent) 2

Off-label use includes adult-onset Still’s disease (AOSD), sharing pathophysiology with sJIA; colchicine-resistant familial Mediterranean fever (FMF); and other periodic fever syndromes.

Aging-relevant evidence

Type 2 diabetes and beta-cell function

The most quantitatively striking aging-relevant finding: Larsen et al. (2007 NEJM) randomised 70 patients with type 2 diabetes (34 anakinra, 35 placebo) to anakinra 100 mg/day SC vs placebo for 13 weeks 3. Results:

  • HbA1c decreased by 0.46 percentage points more in the anakinra arm than placebo (95% CI 0.01–0.90; P=0.03).
  • Proinsulin/insulin ratio fell in the anakinra group (P=0.005), and C-peptide AUC (oral glucose tolerance test + IV stimulation combined) increased (P=0.05), directly indexing beta-cell secretory improvement; insulin sensitivity was unchanged on clamp (P=0.58) and HOMA-based analysis (P=0.60) — locating the benefit at the beta cell, not peripheral tissues.
  • IL-6 and CRP fell significantly (P<0.001 and P=0.002 respectively at 13 weeks), confirming IL-1 blockade reduced systemic inflammation.
  • Injection-site reactions occurred in 17/34 (50%) anakinra-treated patients vs 0/35 placebo patients; no patient discontinued due to adverse events. No symptomatic hypoglycaemia was observed.

The mechanistic interpretation is that pancreatic islet IL-1β (produced locally in response to high-glucose and lipid stress) is a driver of beta-cell dysfunction in T2D — anakinra corrects this local inflammasome-mediated cytotoxicity. This is not a general insulin-sensitising mechanism (contrast with metformin). The finding remains under-replicated at longer durations; the 13-week window does not establish durability. needs-replication long-term-unknown

DimensionStatus
Pathway conserved in humans?yes (trial enrolled humans)
Phenotype conserved in humans?yes (HbA1c endpoint)
Replicated in humans?limited (single trial, n=70, 13 weeks)

Cardiovascular disease — post-STEMI heart failure prevention

A programme of pilot and pooled analyses by Abbate and colleagues (the VCU-ART series) has tested anakinra in ST-segment-elevation MI (STEMI):

Pooled analysis of VCUART 1 and 2 (n=139 total; 84 anakinra, 55 placebo) found that anakinra significantly reduced the composite of all-cause death or new-onset heart failure at one year: 8.2% vs 29.1% (log-rank P=0.002) 4. CRP area-under-the-curve decreased from 222.82 to 75.48 mg·day/L (P<0.001), confirming IL-1 blockade. Injection-site reactions were more common with anakinra (22.6% vs 5.5%); serious infection rates were comparable. This mechanistic rationale — IL-1-driven peri-infarct inflammation amplifies myocardial injury and remodelling — aligns with the nlrp3-inflammasome → IL-1β → cardiomyocyte apoptosis axis.

The VA-ART4 trial (NCT05177822) is currently active, not recruiting — a larger powered test of this hypothesis. needs-replication

DimensionStatus
Pathway conserved in humans?yes (human STEMI trial)
Phenotype conserved in humans?yes (HF + death endpoints)
Replicated in humans?in-progress (pooled pilots; VA-ART4 ongoing)

Atherosclerosis and inflammaging context

Ridker (2016 review, Circ Res) noted that small ischaemia studies demonstrated reductions in acute-phase hsCRP with anakinra, contextualising it within the chronic-inflammation therapeutics landscape alongside canakinumab and colchicine 5. However, no anakinra trial has replicated the scale of CANTOS (n=10,061) for cardiovascular event endpoints in a primary- or secondary-prevention population. The key point: CANTOS established the IL-1β hypothesis; whether simultaneous IL-1α suppression (via anakinra’s receptor-level blockade) adds incremental cardiovascular protection is formally untested. needs-human-replication

Aortic aneurysm — cautionary signal

A murine study found that pharmacological IL-1α disruption (which anakinra would also achieve) worsened abdominal aortic aneurysm (AAA) expansion 6. If this IL-1α-specific AAA-protective effect translates to humans, anakinra’s dual IL-1α + IL-1β blockade could be counterproductive in patients with AAA — in contrast to the presumably safer IL-1β-selective canakinumab. This is a preclinical signal only and has not been confirmed in human AAA trials, but warrants flagging. needs-human-replication contradictory-evidence

Comparison to canakinumab

FeatureAnakinraCanakinumab
MechanismCompetitive IL-1R1/IL-1R2 antagonistIL-1β neutralising monoclonal antibody (IgG1κ)
IL-1α coverageYes — both IL-1α and IL-1β blockedNo — IL-1α signalling intact
Molecular weight~17.3 kDa~145 kDa
Half-life~6–8 hours~26 days
Dosing schedule100 mg/day SC50–300 mg q3mo SC
Patient burdenHigh (daily injections)Low (4 injections/year)
Approved (aging-adjacent)RA, NOMID, sJIA, pericarditisCAPS, TRAPS, FMF, sJIA
CANTOS-class RCTNone (VCU-ART pooled n=139)CANTOS n=10,061
Infection risk (human trial)Injection-site reactions; serious infections comparable to placebo in VCU-ARTFatal infection/sepsis excess: 0.31 vs 0.18/100 PY (P=0.02) in CANTOS
Annual cost (list price)~$20,000–30,000 USD (RA dose, biosimilar available)~$150,000–200,000 USD (orphan pricing)
Biosimilar availabilityYes (Kineret biosimilars entering market)No
SASP suppression hypothesisStronger (blocks IL-1α, the paracrine SASP amplifier)Weaker (IL-1β only)

The cost and dosing-burden profile positions anakinra as more tractable for a chronic prevention trial than canakinumab, provided the daily-injection burden can be managed. Biosimilar entry may further reduce cost.

Translation gap — aging-specific

Despite FDA approval and a substantial safety record in inflammatory diseases, anakinra has no Phase 3 trial for any aging-indication (atherosclerosis prevention, frailty, biological-age deceleration). Several barriers mirror canakinumab:

  1. Infection risk. Daily IL-1 receptor blockade chronically impairs an important innate immune axis. The VCU-ART data showed injection-site reactions dominated; serious infection was comparable to placebo in those small trials, but longer-duration / larger-scale use could reveal a signal analogous to (or exceeding) canakinumab’s CANTOS sepsis excess. long-term-unknown
  2. Daily injection burden. For a healthy aging individual, 365 injections/year is a near-insurmountable adherence barrier without continuous clinical support. Long-acting formulations or delivery systems would be required for population-level prevention.
  3. No aging-endpoint evidence. No trial has measured biological-age clocks, frailty indices, or lifespan as outcomes for anakinra.
  4. Translation-gap category: phase-3-rct-needed — the mechanism is human-validated, the safety is characterised, but no RCT in an aging-primary-prevention population exists.

Next experiment: Long-duration RCT (≥2 yr) with biological-age clock endpoints + cardiovascular event adjudication in community-dwelling adults ≥65 with elevated hsCRP (≥2 mg/L) and no prior MI — modelled on CANTOS but enrolling pre-morbid individuals; would resolve whether dual IL-1α/IL-1β blockade extends the CANTOS MACE signal to a primary-prevention population.

Cross-references

Active clinical trials (ClinicalTrials.gov, 2026-05-07)

As of 2026-05-07 re-query, 29 trials with anakinra as the intervention are RECRUITING or ACTIVE_NOT_RECRUITING across all indications. The three most aging-relevant are listed below; the broader set spans sepsis, pericarditis, dengue hyperinflammation, osteoarthritis, CAR-T toxicity, and other inflammatory conditions.

NCTTitleStatusCondition
NCT06336733Colchicine-resistant FMF: on-demand anakinra vs standard careRECRUITINGFamilial Mediterranean Fever
NCT05814159Anakinra in Japanese patients with Still’s disease (sJIA + AOSD)ACTIVE_NOT_RECRUITINGsJIA / AOSD
NCT05177822VA-ART4: IL-1 blockade in acute MI to prevent heart failureACTIVE_NOT_RECRUITINGHeart failure post-STEMI

None of the active trials are for aging-specific endpoints. VA-ART4 is the most aging-relevant (cardiovascular prevention in a post-MI population).

Limitations and open questions

  • Dual IL-1α/IL-1β blockade — is stronger necessarily better for aging? Anakinra should in principle produce more complete SASP suppression than canakinumab (by blocking IL-1α, the paracrine SASP amplifier). This prediction has not been directly tested in a human aging trial. needs-human-replication
  • Aortic aneurysm signal. Murine evidence suggests IL-1α blockade worsens AAA 6. If confirmed in humans, anakinra would be contraindicated in patients with aortic pathology — an important safety stratification question. needs-human-replication
  • Long-term infection risk under sustained daily blockade. The VCU-ART trials (total n=139; ~3–12 months) are too small and short to detect the fatal-sepsis signal seen in CANTOS (n=10,061; median 3.7 years). long-term-unknown
  • PubChem CID: null — not applicable for this recombinant protein biologic; verify whether a PubChem cross-reference biologics entry exists. needs-canonical-id
  • Molecular formula verification. The formula C759H1186N208O232S10 requires cross-check against primary characterisation documentation. needs-verification
  • No biomarker-guided patient selection strategy for the aging-prevention indication (analogous gap to canakinumab). unsourced

Footnotes

Footnotes

  1. bresnihan-1998-anakinra-ra · n=472 randomised (placebo + three anakinra doses) · rct · 150 mg/day arm: significant reduction in joint swelling, morning stiffness; first biologic demonstrating beneficial effect on joint erosion rate · model: RA patients (adults) · doi:10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.0.CO;2-2 · PDF not downloaded (status: not_oa) ↩

  2. brucato-2016-airtrip-pericarditis · n=21 randomised · rct · anakinra reduced pericarditis recurrence to 18.2% vs 90% placebo (P<0.001); median flare-free survival not reached in anakinra arm · model: colchicine-resistant / corticosteroid-dependent recurrent pericarditis patients · doi:10.1001/jama.2016.15826 · PDF not downloaded (status: pending) ↩

  3. larsen-2007-anakinra-t2d · n=70 randomised (34 anakinra, 35 placebo); 67 completed (34 anakinra, 33 placebo) · rct · 13 weeks · HbA1c between-group difference: −0.46 percentage points (95% CI 0.01–0.90; P=0.03); proinsulin/insulin ratio reduced (P=0.005); C-peptide AUC enhanced (oral+IV combined P=0.05); IL-6 (P<0.001) and CRP (P=0.002) reduced; insulin sensitivity unchanged (clamp P=0.58, HOMA P=0.60); transient injection-site reactions: 17/34 anakinra vs 0/35 placebo · model: type 2 diabetes patients (adults, age ~60, BMI ~31) · doi:10.1056/NEJMoa065213 · PDF locally available ↩

  4. abbate-2022-vcuart-pooled · n=139 (84 anakinra, 55 placebo); pooled from VCUART 1 + 2 + 3 pilot RCTs · rct (pooled) · all-cause death or new-onset HF: 8.2% vs 29.1% (log-rank P=0.002); CRP AUC: 75.48 vs 222.82 mg·day/L (P<0.001) · model: STEMI patients (adults) · doi:10.1093/ehjcvp/pvab075 · PDF not downloaded (status: pending) ↩

  5. ridker-2016-circ-res-review · review · model: human atherosclerosis / inflammaging context · doi:10.1161/CIRCRESAHA.115.306656 · PDF not downloaded (status: pending) ↩

  6. salmon-2022-il1a-aaa-mice · in-vivo · genetic and pharmacological IL-1α disruption worsened aortic aneurysm in murine AAA model · model: mouse aortic aneurysm · doi:10.1016/j.avsg.2022.05.024 · PDF not downloaded (status: pending) ↩ ↩2

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