Primary biliary cholangitis (PBC)
Autoimmune cholestatic liver disease — chronic non-suppurative destructive cholangitis of intralobular bile ducts. AMA (anti-mitochondrial antibody) positive ~95%, anti-sp100 / anti-gp210 in AMA-negative ~5%. Female predominance ~10:1. UDCA first-line since the 1990s with treat-to-target ALP <1.67x ULN per POISE / Paris II at 12 months. 2024 PPAR-agonist paradigm: elafibranor (Iqirvo PPAR α/δ FDA June 2024) and seladelpar (Livdelzi PPAR δ FDA August 2024). Obeticholic acid (Ocaliva FXR agonist FDA 2016) restricted to non-cirrhotic patients after September 2024 FDA boxed-warning action. Bezafibrate off-label per BEZURSO + EASL 2017 endorsement. Pruritus ladder (cholestyramine → rifampin → naltrexone → sertraline; plasmapheresis refractory). DEXA + bisphosphonates for cholestasis-osteoporosis. Fat-soluble vitamin replacement. HCC surveillance every 6 months once cirrhotic. Liver transplant for end-stage. EASL 2017 + AASLD 2018 guidelines. The editorial honest answer for this trigger is that no peptide in the Juno library has a defensible discovery-card case.
What changes during this transition
PBC is one of the cleanest standard-of-care stories in hepatology — UDCA since the 1990s, two PPAR-agonist FDA approvals in 2024 (elafibranor June, seladelpar August), obeticholic acid now restricted to non-cirrhotic patients after the September 2024 FDA action, and treat-to-target ALP <1.67× ULN per POISE/Paris II at 12 months. Diagnosis: AMA (anti-mitochondrial antibody) positive in ~95% of cases (targeting pyruvate dehydrogenase complex E2 subunit / PDC-E2 on the inner mitochondrial membrane), anti-sp100 / anti-gp210 in the AMA-negative ~5%. Female predominance is ~10:1. Disease progression risk includes cirrhosis, hepatocellular carcinoma, end-stage liver disease requiring transplant. Standard-of-care backbone: **UDCA (ursodeoxycholic acid)** has been Tier 1 first-line since the 1990s, with treat-to-target ALP <1.67× ULN with normal bilirubin at 12 months per POISE / Paris II criteria. UDCA response at 12 months is the load-bearing decision point — a UDCA responder stays on monotherapy; an inadequate responder escalates to second-line. Second-line additions (UDCA-inadequate responders): - **Obeticholic acid (Ocaliva, FXR agonist, FDA 2016)** — now restricted to non-cirrhotic patients after the September 2024 FDA boxed-warning action after hepatotoxicity / death signals in Child-Pugh B/C populations - **Elafibranor (Iqirvo, PPAR α/δ dual agonist, FDA June 2024)** — first 2024 PPAR-agonist approval - **Seladelpar (Livdelzi, PPAR δ agonist, FDA August 2024)** — second 2024 PPAR-agonist approval - **Bezafibrate** off-label per BEZURSO trial + EASL 2017 endorsement (often cheaper and more accessible than the newer PPAR agonists) - **Fenofibrate** off-label with similar PPAR-α framing Adjunctive care: pruritus management ladder (cholestyramine first, then rifampin, naltrexone, sertraline; plasmapheresis for refractory). DEXA at diagnosis + bisphosphonates if indicated for cholestasis-related osteoporosis. Fat-soluble vitamin replacement (A, D, E, K) in advanced cholestasis. HCC surveillance with abdominal ultrasound ± AFP every 6 months once cirrhotic. Liver transplant for end-stage cirrhosis. Guidelines: EASL 2017 + AASLD 2018 are the cross-jurisdictional anchors. POISE / Paris II treat-to-target is the load-bearing biomarker target. Where Juno's library fits — narrowly and with deliberate non-elevation. No peptide has a discovery-card-defensible PBC case. The five drafted substrate entries (BPC-157, TB-500, NMN, Thymosin alpha-1, GHK-Cu) exist for honest /ask answers when users probe. BPC-157's Sikiric Croatia rodent liver-injury data (CCl4, paracetamol, restraint-stress models) is acute hepatocellular toxin exposure — it does not translate to chronic autoimmune destruction of intralobular bile ducts. TB-500's actin-sequestration and tissue-repair handwaves don't engage bile-acid pool modulation, FXR signaling, or PPAR signaling — the load-bearing pathways. NMN's mitochondrial framing has surface appeal via the AMA-PDC-E2 connection but conflates autoimmune autoantigen recognition with NAD+ depletion — different layers. Thymosin alpha-1 has the most plausible-on-paper mechanism story (T-cell modulation, and PBC's pathology involves autoreactive CD4+ and CD8+ T-cell destruction of biliary epithelium) but Rule 6 hits hard: the hepatitis-B registered indication does NOT propagate to autoimmune cholangiopathy because the T-cell pathology is autoreactive in PBC versus anti-viral in HBV, and modulating it carries different risk. GHK-Cu's TGF-β / tissue-remodeling framing has theoretical fit with periportal fibrosis but no human PBC data, and the copper exposure in cholestatic liver disease is a specific concern given that cholestasis disrupts hepatobiliary copper excretion. The honest editorial frame: hepatologist coordination, POISE / Paris II treat-to-target UDCA response, the 2024 PPAR-agonist second-line ladder, OCA cirrhosis-restriction awareness post-September 2024, pruritus management ladder, DEXA / bisphosphonate / fat-soluble vitamin / HCC-surveillance adjunctive care, and EASL 2017 + AASLD 2018 guidelines drive outcomes; no peptide substitutes.
Important caveat
PBC is hepatology-managed autoimmune cholestatic liver disease — AMA (~95%) + anti-sp100 / anti-gp210 (AMA-negative) for diagnostic confirmation; ALP + GGT + total bilirubin + AST/ALT for monitoring; transient elastography or MRE for fibrosis staging; DEXA at diagnosis for cholestasis-osteoporosis baseline. No peptide substitutes for this care framework. UDCA (ursodeoxycholic acid) has been Tier 1 first-line since the 1990s with treat-to-target ALP <1.67× ULN with normal bilirubin at 12 months per POISE / Paris II criteria — this biomarker target is the LOAD-BEARING decision point. UDCA response: stays on monotherapy. UDCA-inadequate response: second-line escalation. Second-line options: obeticholic acid (Ocaliva, FXR agonist, FDA 2016) — RESTRICTED to non-cirrhotic patients after the September 2024 FDA boxed-warning action following hepatotoxicity / death signals in Child-Pugh B/C populations; elafibranor (Iqirvo, PPAR α/δ dual agonist, FDA June 2024); seladelpar (Livdelzi, PPAR δ agonist, FDA August 2024); bezafibrate off-label per BEZURSO + EASL 2017 endorsement (often cheaper / more accessible than newer PPAR agonists). Pruritus management ladder: cholestyramine first, then rifampin, naltrexone, sertraline; plasmapheresis for refractory. DEXA + bisphosphonates for cholestasis-osteoporosis. Fat-soluble vitamin replacement (A, D, E, K) in advanced cholestasis. HCC surveillance with abdominal ultrasound ± AFP every 6 months once cirrhotic. Liver transplant for end-stage. EASL 2017 + AASLD 2018 guidelines are cross-jurisdictional anchors. No Juno library peptide is surfaced as a PBC discovery card. Rule 6 non-propagation is editorially load-bearing on this trigger: BPC-157's Sikiric Croatia rodent liver-injury corpus is acute hepatocellular toxin exposure and does NOT propagate to chronic autoimmune destruction of intralobular bile ducts; TB-500's tissue-repair framing does NOT engage bile-acid pool / FXR / PPAR signaling; NMN's general-aging NAD+ framing has surface appeal via AMA-PDC-E2 mitochondrial connection but autoimmune autoantigen recognition is NOT NAD+ depletion; Thymosin alpha-1's hepatitis-B Tier 1 registered indication does NOT propagate to autoimmune cholangiopathy — autoreactive T-cell pathology has different risk profile than anti-viral T-cell modulation; GHK-Cu's cosmetic-dermatology TGF-β framing does NOT propagate to autoimmune hepatic fibrosis, and copper handling in cholestasis is a specific concern. Pregnancy: UDCA is the preferred therapy in pregnancy (extensive safety data); PBC pregnancies require hepatology + maternal-fetal medicine coordination; intrahepatic cholestasis of pregnancy is a distinct entity that PBC patients can develop superimposed on baseline disease. WADA athletes: BPC-157 (S0) and TB-500 (S2) prohibited at all times. Multi-jurisdictional clinical use: UDCA, elafibranor, seladelpar approved across major jurisdictions; obeticholic acid approval restricted post-September 2024.
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