Linvesirixibat (Lynavoy)

FDA approved: March 19, 2026 | Brand name: Lynavoy | Target: ASBT (apical sodium-bile acid transporter) | Indication: Cholestatic pruritus in adult PBC patients | Form: 40 mg film-coated tablet | Dose: 40 mg BID, fasted | PMIDs: 41173016, 36343847, 34625435, 40998033, 38780109, 33534626, 33383036, 23524965, 25194674, 7617459, 30104765

TL;DR

Linvesirixibat (Lynavoy) is a first-in-class ASBT inhibitor — the first drug ever approved specifically for cholestatic pruritus in PBC. It works locally in the gut (0.05% bioavailability) by blocking ileal bile acid reabsorption, reducing the enterohepatic bile acid pool, and lowering serum bile acids that drive itch via TGR5/TRPA1 nerve signaling. The Phase 3 GLISTEN trial (PMID 41173016) showed a statistically significant but modest benefit: −0.71 points on the 0–10 WI-NRS scale vs placebo (p=0.001); 56% of linerixibat patients achieved ≥3-point reduction vs 43% on placebo (NNT ≈ 8). Diarrhea is the dominant side effect (61% any grade; 4% discontinuation). The drug is expensive (~ $45, 000-60, 000 + / ye a res t .) v s g e n er i c a lt er na t i v es (b ez a f ib r a t e$ 20–50/month) with no head-to-head comparison. Wearable pruritus monitoring is not clinically validated; sleep disruption from nocturnal itch is the most tractable wearable proxy.

Why it matters for Vitals

Nocturnal itch disrupts sleep architecture — PBC patients with severe pruritus have EQ-5D-5L health utility scores comparable to severe Parkinson’s disease; nocturnal scratching is detectable via actigraphy and HRV degradation on consumer wearables
Wearable pruritus detection is research-grade only — no validated commercial product exists; accelerometry-based scratch detection is used in clinical trials but not in consumer devices
HRV and sleep staging as treatment-response proxies — if nocturnal itch improves with linerixibat, wearable-tracked sleep efficiency and HRV recovery may show downstream improvement, but no validated clinical threshold exists for this inference
Liver function monitoring is standard care — ALP, bilirubin, ALT/AST tracking is indicated for PBC patients regardless of linerixibat use; wearable-ready biomarker panels for liver health are emerging but not yet actionable
Affordability and adherence are real-world confounds — diarrhea-driven discontinuation and cost-vs-generic decisions affect whether a patient actually benefits; Vitals should flag non-response workups to assess adherence and tolerability first
No metabolic or GLP-1 application is warranted — ASBT inhibition’s effect on glucose metabolism or GLP-1 activity is unstudied; CGM tracking for this indication is speculative

Key Facts

Item	Detail
Brand	Lynavoy
Class	ASBT (apical sodium-bile acid transporter / IBAT) inhibitor
FDA approval date	March 19, 2026
Indication	Cholestatic pruritus in adults with PBC
Mechanism	Blocks ileal bile acid reabsorption → fecal bile acid loss → reduced portal bile acid return → lower serum bile acids → less TGR5/TRPA1-mediated itch signaling
Formulation	40 mg film-coated tablet
Dosing	40 mg BID; fasted (≥30 min before food); cannot be crushed
Bioavailability	0.05% absolute oral; acts locally in GI tract
Elimination	~80% biliary/fecal as unchanged parent; ~20% renal as unchanged parent
Half-life	Oral 6.76 hours (flip-flop kinetics); IV 0.8 hours
Key PD effects	↓TSBA, ↓FGF19, ↑C4 (bile acid synthesis marker); effects evident by week 4, sustained at week 24
Drug interactions	Separate ≥4 hours from bile acid sequestrants (cholestyramine, colestipol, colesevelam); no CYP450 interactions expected
Cost	Est. $45, 000-60, 000 + / ye a r (n o g e n er i c); v s b ez a f ib r a t e$ 20–50/month generic

Mechanism Summary

ASBT Biology

ASBT (SLC10A2 / IBAT) is the primary Na⁺-coupled transporter mediating intestinal bile acid reabsorption in the ileum, accounting for ~95% of enterohepatic bile acid recirculation. Bile acids bind to IBABP, are transported to the basolateral membrane, and efflux via OSTα/OSTβ into portal circulation returning to the liver. (PMID 16319831 — confirmed)

ASBT Inhibition

Linvesirixibat blocks ASBT → bile acids remain in the intestinal lumen → increased fecal bile acid excretion → depletion of the enterohepatic pool → reduced portal bile acid return → decreased serum total bile acids. The drug exhibits absorption-limited flip-flop pharmacokinetics: oral half-life (6.76 h) exceeds IV half-life (0.8 h), indicating absorption rate limits elimination. (PMID 34625435 — confirmed)

FGF19 Direction — Correcting the Narrative

ASBT inhibition reduces ileal bile acid uptake → diminished FXR-mediated FGF19 induction → partial relief of CYP7A1 suppression → compensatory increase in bile acid synthesis. FGF19 is suppressed, not elevated. This contradicts earlier mechanistic narratives that cited elevated FGF19 as a therapeutic goal. The NGM282 (aldafermin) FGF19 analog was terminated due to neoplasia signals — directly relevant because it demonstrates that direct FGF19 elevation is genuinely dangerous. Linvesirixibat moves FGF19 in the opposite direction. (PMID 32561423; GLISTEN PD data — confirmed)

Cholestatic Pruritus Pathways

Cholestatic itch is multifactorial (PMID 33534626 — confirmed):

Bile acids → TGR5 → TRPA1: Bile acids activate TGR5 on cutaneous sensory nerve endings → Gαs → cAMP → PKA → itch. This is the primary pathway ASBT inhibitors target. (PMID 23524965, 25194674)
Lysophosphatidic acid (LPA) via autotaxin: ATX converts LPC to LPA → activates LPA receptors on sensory neurons → itch signaling. ATX is elevated in cholestatic pruritus and correlates with itch severity.
Endogenous opioids: Cholestasis upregulates central μ-opioid receptor tone → naltrexone/naloxone provide itch relief. (PMID 7617459)
Bilirubin → MRGPRX4: Contributes to itch in cholestasis.

Histamine is NOT involved — antihistamines are ineffective for cholestatic pruritus.

Why the Bile Acid–Pruritus Correlation Is Weak

Multiple studies confirm no direct correlation between serum bile acid levels and pruritus intensity (PMID 38780109). Baseline TSBA does not predict ASBT inhibitor response. Change in TSBA shows only moderate correlation with pruritus improvement (r=0.52; individual biomarker correlations r ≤ 0.3). 40% of “biochemical responders” (≥30% TSBA reduction) had no pruritus benefit. The pruritus benefit from ASBT inhibition may operate partly through mechanisms other than bile acid lowering per se.

Reversibility

Linvesirixibat shows reversible ASBT inhibition upon washout in vitro. Maralixibat and odevixibat show sustained inhibition even after drug washout (PMID 40998033). Clinical significance of this pharmacological difference is not established.

Clinical Evidence

GLISTEN Phase 3 (PMID 41173016) — Pivotal; Confirmed

Design: Randomized, double-blind, placebo-controlled; N=238 adults with PBC and moderate-to-severe cholestatic pruritus (mean baseline WI-NRS ~6.5–7.0); stable background anti-itch therapy permitted; 19 countries.

Primary endpoint: Mean change from baseline in monthly WI-NRS score over 24 weeks.

Result: LS mean change −2.86 linerixibat vs −2.15 placebo; difference −0.71 points (95% CI: −1.15, −0.28), p=0.001

Responder analysis:

Threshold	Linerixibat	Placebo	NNT
≥2-point reduction	68%	64%	—
≥3-point reduction	56%	43%	~8
≥4-point reduction	41%	29%	~8

Secondary endpoints: Itch-related sleep interference p=0.024 (favoring linerixibat); significant at week 2 (rapid onset).

GLIMMER Phase 2b (PMID 36343847) — Confirmed (per-protocol; ITT null)

Dose-ranging RCT across 5 arms (20 mg QD, 90 mg QD, 180 mg QD, 40 mg BID, 90 mg BID); 4-week run-in, 12-week double-blind, 4-week run-out. Dose-dependent pruritus reduction in per-protocol analysis (significant for 180 mg QD, 40 mg BID, 90 mg BID vs placebo). Did NOT meet primary endpoint in ITT population — attributed to high placebo response. Established 40 mg BID as the optimal registered dose.

Maralixibat PBC Phase 2 (PMID 30859149) — Failed; Contested

Maralixibat (same target) 10 or 20 mg/day for 13 weeks: LS mean change −26.5 vs −23.4 placebo; P=0.48, not statistically significant. Both groups had large reductions. Establishes that ASBT inhibition does not reliably treat PBC pruritus in all contexts.

Biomarker Correlations — Weak (PMID 38780109; PMID 41173016)

GLISTEN showed significant reductions in TSBA, autotaxin (ATX), and IL-31. However individual biomarker correlations with pruritus improvement were weak (r ≤ 0.3). Only 60% of patients achieving ≥30% TSBA reduction were pruritus responders — meaning 40% had no symptom benefit despite biochemical response.

Bezafibrate Comparison (PMID 33383036) — FITT Trial

Bezafibrate 55% vs 11% placebo for ≥50% pruritus reduction in PBC/PSC patients. At generic pricing (~ $20-50/ m o n t h v s .$ 45,000–60,000+/year for linerixibat), bezafibrate is a substantially more affordable option. No head-to-head comparative effectiveness trial exists.

Comparative Landscape

Comparator	Key Finding	Evidence Grade
vs. Placebo	WI-NRS −0.71 points, p=0.001 (GLISTEN)	Confirmed
vs. Bezafibrate (FITT)	Bezafibrate 55% vs 11% placebo; no head-to-head	Contested
vs. Rifampin	Rifampin: multiple small RCTs positive; distinct mechanism (PXR activation)	Confirmed
vs. Naltrexone	Naltrexone: ~45% had >50% pruritus reduction in RCTs	Confirmed
vs. Sertraline	Sertraline 75–100 mg: modest efficacy; small RCTs	Supported
vs. Cholestyramine	Weak evidence; only 56 PBC patients studied	Supported
vs. OCA	OCA worsens pruritus in many PBC patients (POISE trial)	Confirmed
vs. Maralixibat (PBC)	Maralixibat FAILED primary endpoint (P=0.48) vs. linerixibat success	Confirmed

Cost context: Generic rifampin ( ~~$20-50/ m o n t h), na lt re x o n e ($ 30–80/month), sertraline (~~ $10-30/ m o n t h), b ez a f ib r a t e ($ 20–50/month) vs. linerixibat (est. $45,000–60,000+/year). No cost-effectiveness analysis vs. off-label alternatives exists.

Formulation and Delivery

Drug	Formulation	Administration
Linvesirixibat (Lynavoy)	40 mg film-coated tablet	Fasted, BID; cannot be crushed
Maralixibat (Livmarli)	Oral solution (9.5 mg/mL) + tablet	30 min before meals; requires refrigeration
Odevixibat (Bylvay)	Hard capsule (400/1200 mcg) + pellets	Can be opened; high-fat meal reduces Cmax 72%, AUC 62%

Note: Linvesirixibat’s inability to be crushed distinguishes it from odevixibat in patients with swallowing difficulties. No enteric coating — drug acts locally via minimal systemic absorption.

Safety and Risks

GLISTEN Phase 3 Safety (24 weeks; PMID 41173016)

Adverse Event	Linerixibat	Placebo
Diarrhea (any grade)	61%	—
Abdominal pain	18%	—
Discontinuation: diarrhea	4%	<1%
Discontinuation: abdominal pain	4%	0%
Serious adverse events	12%	3%
Deaths	0	0

Class Safety Signals — FDA 2025 Updates

New contraindication (June 2025): FDA added contraindication for maralixibat and odevixibat in patients with prior or active hepatic decompensation events (variceal hemorrhage, ascites, hepatic encephalopathy) — based on post-marketing safety data in PFIC and Alagille syndrome. Not yet applied to linerixibat label (different indication/population).
Hepatotoxicity warning: Treatment-emergent liver test elevations and potential DILI observed in PFIC/Alagille syndrome trials.
Fat-soluble vitamin deficiency: Maralixibat can cause vitamins A, D, E, K deficiency (bleeding risk added to labeling in 2025).
Class-level vigilance is warranted for linerixibat; specific warnings have not yet been applied.

FGF19 Carcinogenesis Risk — Animal Data; Human Risk Unknown

Transgenic mice with FGF19 overexpression develop hepatocellular carcinomas at 10–12 months (PMID 30104765)
NGM282 (aldafermin, engineered FGF19 analog) was terminated due to neoplasia signals in clinical trials
Linvesirixibat suppresses FGF19 — moving in the opposite direction from NGM282
No human carcinogenicity signal demonstrated at therapeutic ASBT inhibitor doses
Long-term (>2 year) human safety data for linerixibat in adult PBC are absent

Key Safety Summary

Diarrhea is the dominant side effect and primary discontinuation driver
No evidence linerixibat causes the hepatic decompensation seen with maralixibat/odevixibat in fragile populations
The FGF19 carcinogenesis concern is real in animal models but unconfirmed in humans at current dose exposure
Long-term safety beyond 2 years is a data gap

Vitals Relevance

Wearable Pruritus Monitoring — Research Grade Only

No validated commercial wearable product exists for pruritus detection or monitoring. Accelerometry-based scratching detection has been used in clinical trials but is not available in consumer devices. Vitals should not operationalize pruritus detection from wearable data without clinical validation.

Nocturnal Itch → Sleep Disruption (Tractable Proxy)

Severe PBC pruritus causes significant nocturnal scratching and sleep disruption. Consumer wearables (Apple Watch, Oura, Whoop) can track:

Sleep efficiency degradation — nocturnal pruritus reduces sleep efficiency; improvement may correlate with treatment response
HRV suppression — acute sleep disruption lowers overnight HRV; sustained improvement may serve as a downstream proxy for pruritus control
Actigraphy — motion data may capture nocturnal scratching episodes in research settings

No validated clinical threshold exists for using wearable sleep metrics to assess linerixibat treatment response.

Liver Function Monitoring

Standard clinical care for PBC patients on linerixibat includes ALP, bilirubin, ALT/AST at regular intervals. Wearable-ready liver health biomarkers are an emerging area but not yet actionable for Vitals interpretation.

Metabolic / GLP-1 Axis — Speculative, Do Not Implement

ASBT inhibition reduces bile acid flux to the portal system. Whether this measurably affects glucose metabolism or GLP-1 activity is unstudied. CGM tracking for metabolic effects of linerixibat is not warranted.

Adherence and Side Effect Assessment First

Before attributing non-response to biological factors, Vitals should flag:

Is the patient tolerating linerixibat? (Diarrhea is the most common reason for discontinuation)
Is the patient taking it correctly? (Fasted state, BID dosing, ≥4 hours from bile acid sequestrants)
Is cost/access a barrier? (Affordability vs generic alternatives)

Coaching Boundaries

Do not suggest linerixibat is a cure or reliable pruritus treatment — the clinical benefit is statistically significant but modest; 43% of placebo patients achieved clinically meaningful reduction
Do not use bile acid or FGF19 biomarker levels to assess treatment response — correlations with symptom improvement are too weak for individual decision-making
Do not recommend ASBT inhibitors for PSC, biliary atresia, or any indication other than approved PBC pruritus — no ASBT/IBAT inhibitor is approved for these populations
Do not suggest linerixibat for metabolic/weight-loss purposes — no evidence supports this; effect on GLP-1 axis is unstudied
Do cite generic alternatives fairly — bezafibrate, rifampin, naltrexone, and sertraline all have some evidence for cholestatic pruritus at substantially lower cost; the choice involves clinical judgment, not just efficacy
Flag the high placebo response — patients may have high expectancy effects; objective sleep and itch diary tracking is more reliable than subjective recall
Acknowledge the multifactorial nature of cholestatic pruritus — ASBT inhibition addresses the bile acid pathway only; other itch mediators (LPA, opioids, bilirubin) may dominate in non-responders

Implementation / Evidence-Backed Actions

Evidence boundary: No validated commercial wearable exists for pruritus monitoring. No biomarker reliably predicts which PBC patients will respond to linerixibat. Do not operationalize genetic testing, wearable detection, or biomarker-driven dosing without clinical validation.

Evidence-Backed Actions

Daily itch diary (WI-NRS or ItchRO): Patient-reported outcomes remain the gold standard for pruritus assessment. e-diary apps could improve adherence to daily logging. (Evidence grade: confirmed gold standard)
Sleep monitoring via consumer wearable: Nocturnal pruritus disrupts sleep — HRV and actigraphy sleep staging from Apple Watch/Oura/Whoop could serve as a proxy for treatment response in research or patient self-monitoring. No validated clinical threshold exists. (Evidence grade: proxy, research-grade)
Liver function monitoring: Standard clinical care — ALP, bilirubin, ALT/AST at regular intervals for PBC patients on linerixibat. (Evidence grade: confirmed)
Assess adherence and side effects first: Before attributing non-response to genetic or biological factors, confirm the patient is tolerating linerixibat (diarrhea is the most common reason for discontinuation). (Evidence grade: confirmed clinical practice)

Proxy Actions (caveat required)

Accelerometer-based scratching detection: Research-validated in itch trials; no commercial clinical product available. Could theoretically be used in a trial or research setting.
Serum bile acid levels: Can track biochemical response but correlation with symptom improvement is too weak (r ≤ 0.3) for individual treatment decisions.

Do Not Implement

CGM or metabolic tracking for GLP-1/bile acid axis effects: ASBT inhibition’s effect on glucose metabolism or GLP-1 activity is unstudied. No Vitals metabolic application is warranted.
Polygenic risk scores for PBC or pruritus response: Not developed.
Serum bile acid-driven dosing: TSBA does not reliably predict response (r ≤ 0.3).

Substances (01-Substances)

Berberine — AMPK activator with distinct metabolic and microbiome mechanisms; no ASBT overlap
Rapamycin — mTORC1 inhibitor; different liver safety profile and indication
Semaglutide Liver Health MASLD MASH — overlapping PBC/liver disease context; different mechanism and indication

Mechanisms (02-Mechanisms)

No existing mechanism note is directly reusable for ASBT or bile acid pruritus — the biology is too specific to this drug class to warrant a shared mechanism note at this time. If a second ASBT inhibitor enters the vault, reassess.

Biometrics (03-Biometrics)

Sleep architecture — general sleep stage patterns; nocturnal pruritus is a cause of sleep disruption that may be tractable via wearable HRV and sleep efficiency tracking
HRV — primary recovery signal; HRV degradation from nocturnal scratching may serve as a downstream treatment-response proxy (research grade only)

Body Systems (02-Body-Systems)

No PBC-specific body system note exists in the vault; the PBC disease context is contained within this hub

Vitals Knowledge Map

Vitals Knowledge Map → Substances section → Linvesirixibat entry added

Last updated: 2026-04-23 | Batch 104 | Vault promotion from KB canonical

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Linvesirixibat