RARE DISEASE
Familial lipoprotein lipase deficiency
Familial lipoprotein lipase deficiency
Familial lipoprotein lipase deficiency
Synonyms: LPL deficiency
Synonyms: LPL deficiency
Synonyms: LPL deficiency
Drug discovery
2
drugs
With orphan designations
Overview
Familial Lipoprotein Lipase Deficiency (LPLD) is a rare autosomal recessive disorder caused by mutations in the LPL gene, leading to impaired triglyceride metabolism. This results in severe hypertriglyceridemia (>2,000 mg/dL), chylomicronemia, and recurrent pancreatitis, often presenting in childhood with abdominal pain, eruptive xanthomas, and hepatosplenomegaly [1][6][7]. Chronic complications include pancreatic damage, diabetes, and neurological symptoms (e.g., depression, memory loss) [1][7]. Diagnosis hinges on genetic testing and absent LPL enzyme activity [6].
Burden
Clinical: Recurrent pancreatitis (50% lifetime risk), chronic pancreatic insufficiency, and retinal lipemia [6][7][15].
Psychosocial: Strict dietary adherence impacts quality of life; 50% report anxiety/depression linked to disease management [4][8].
Economic: Frequent hospitalizations for pancreatitis and lifelong nutritional interventions pose significant healthcare costs [4][8].
Therapies
Dietary: Lifelong restriction of long-chain triglycerides (<20 g/day) with medium-chain triglyceride (MCT) supplementation to reduce chylomicrons [3][7][11].
Monitoring: Regular lipid panels and pancreatic enzyme checks to prevent pancreatitis [7][15].
Emerging: Investigational gene therapy (e.g., alipogene tiparvovec) to restore LPL function [11].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
372 drug discovery papers about Familial lipoprotein lipase deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
372 drug discovery papers about Familial lipoprotein lipase deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-07-14 | Lipoprotein lipase deficiency presenting with gastrointestinal bleeding and compensated shock.
Lipoprotein lipase (LPL) deficiency is an autosomal recessive disorder causing hypertriglyceridemia. Presentations are heterogenous and there are no standardized acute treatment protocols. Long-term management consists of strict dietary control. We report a case of LPL deficiency in an infant presenting with gastrointestinal bleeding and compensated shock, with a more severe presentation than previously published cases. Preliminary diagnosis was based on lipemic blood appearance. Intensive care resuscitation was required. Triglyceride levels peaked above 200 times the upper limit of normal. Insulin infusion provided no benefit. A whole-blood exchange transfusion led to a sustained reduction in triglyceride levels. Diagnosis was confirmed by genetic testing. Despite the magnitude of hypertriglyceridemia, there were minimal end-organ sequelae. The necessity of invasive management of severe hypertriglyceridemia is not established. This case highlights the range of presentations in inherited metabolic disease, and the limited evidence for acute management strategies.
2026-04-02 | Therapeutic plasmapheresis in a young infant with severe hypertriglyceridemia: a case report.
Familial lipoprotein lipase (LPL) deficiency typically occurs during childhood and is characterized by severe hypertriglyceridemia, accompanied by episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. The clearance of chylomicrons from plasma is impaired, causing triglyceride accumulation and giving the plasma a milky/lactescent/lipemic appearance. Symptoms typically resolve when total dietary fat is restricted to 20 g/d. Acute management focuses on maintaining triglyceride levels using insulin, plasmapheresis, blood exchange transfusion, and heparin, although few of these interventions have proven effective in infants. Here, we report a rare case of severe hypertriglyceridemia in a 40-d-old infant who presented with respiratory distress, xanthoma, hepatosplenomegaly, and lipemic samples. Plasmapheresis resulted in a reduction in triglyceride levels and clinical improvement, and further evaluation confirmed a diagnosis of LPL deficiency. Familial LPL deficiency can occur during early infancy, with life-threatening complications. A consensus on the acute management of hypertriglyceridemia in the pediatric population needs to be meticulously established after exploring possible treatment strategies, including plasmapheresis.
2026-01-01 | Sequential Continuous Renal Replacement Therapy and Therapeutic Plasma Exchange in Pediatric Necrotizing Hypertriglyceridemia-Induced Pancreatitis with Suspected Familial Chylomicronemia Syndrome: A Case Report
Background: Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is a severe and underrecognized etiology of pancreatitis, accounting for 1% - 4% of all cases in adults, with extreme triglyceridemia raising the risk of fulminant multi-organ failure. When underlying lipoprotein lipase (LPL) deficiency is suspected—as in familial chylomicronemia syndrome (FCS)—conventional pharmacologic strategies are inherently limited, and therapeutic plasma exchange (TPE) represents the most effective currently available approach for the rapid removal of chylomicrons and triglyceride-rich lipoproteins from the circulation. Case Summary: We report a 14-year-old girl presenting with triglycerides > 14,000 mg/dL, severe necrotizing pancreatitis, acute kidney injury (AKI), mild acute respiratory distress syndrome (ARDS), and metabolic encephalopathy. No prior medical history was identified. Despite aggressive pharmacologic therapy with intravenous insulin, heparin, and fibrates, triglyceride levels remained critically elevated. Continuous renal replacement therapy (CRRT) was initiated for AKI, metabolic acidosis, and hemodynamic instability, achieving significant physiologic stabilization. However, because CRRT does not effectively clear chylomicrons, lipid levels remained dangerously high. Two urgent sessions of TPE reduced triglycerides from >14,000 mg/dL to approximately 300 mg/dL, with subsequent normalization of pancreatic enzymes and full recovery of renal, respiratory, and neurological function. The patient was discharged in good clinical condition. Conclusion: This case illustrates that CRRT and TPE fulfill distinct, non-overlapping roles in severe HTG-AP. CRRT provides essential metabolic bridge support, and TPE achieves definitive lipid clearance. When LPL deficiency is suspected, early escalation to TPE is potentially lifesaving. A high index of clinical suspicion and timely decision-making are the key determinants of outcome in this rare but catastrophic condition.
2025-10-01 | MON-658 When Metabolic Stress Meets Genetics: A Triad of DKA, Acute Pancreatitis, and Hypertriglyceridemia in a Patient with LMF1 Mutation
Abstract Disclosure: S. Abou Khachfe: None. C. Guillen-Lopez: None. A. Patel: None. M. Lonescu: None. Introduction: The combination of diabetic ketoacidosis (DKA), severe hypertriglyceridemia (HTG), and acute pancreatitis (AP) is a rare but critical triad with mortality rates up to 80%. It presents diagnostic and management challenges, often causing metabolic disturbances, organ failure, and prolonged stays. The pathophysiology of this triad is complex, with evidence suggesting a bidirectional relationship. HTG seems to link DKA and AP, though the directionality (DKA→HTG→AP vs. HTG→AP→DKA) remains unclear. In DKA, insulin deficiency promotes lipolysis, increasing free fatty acids (FFA) and very low-density lipoprotein (VLDL) production in the liver, leading to HTG. While moderate HTG is common in DKA, severe HTG (triglycerides >1,000 mg/dL) is rare. In such cases, underlying genetic mutations should be considered. The lipase maturation factor (LMF1) gene encodes a protein essential for lipoprotein lipase (LPL) function, which breaks down triglycerides in chylomicrons and VLDL. Mutations in LMF1 disrupt this process, resulting in severe HTG. Case: A 30-year-old male with poorly controlled T2DM, HTG, and recurrent pancreatitis presented with severe abdominal pain. He had poor adherence to metformin, Jardiance, and pioglitazone, with an A1C of 10.7%. Labs showed lipase 1611 U/L, glucose 238 mg/dL, anion gap 27, beta-hydroxybutyrate 9.7 mmol/L, and triglycerides >2000 mg/dL. He was admitted and treated with IV hydration, insulin infusion, statins, and fenofibrate for euglycemic DKA and HTG-induced AP. Persistently elevated triglycerides >1000 mg/dL required two plasmapheresis sessions, leading to clinical improvement. He was discharged on insulin, atorvastatin, and fenofibrate with a diabetes education referral. Given his recurrent HTG-AP-DKA (>5 episodes), genetic testing for primary HTG was performed, revealing a heterozygous missense mutation in the LMF1 gene (c.1352G>A, p.Arg451Gln). Discussion: AP and DKA are life-threatening conditions with mortality rates reaching 80% when they coexist. Overlapping symptoms and nonspecific amylase and lipase elevations in DKA can complicate diagnosis, leading to poor outcomes. Multidisciplinary collaboration and increased physician awareness are key for optimal management. Current AP severity scoring systems, like Ranson and APACHE II, are impacted by DKA-related factors such as high glucose and low pH, making them less reliable in these cases, highlighting the need for tailored scoring systems, more effective diagnostic algorithms, and specific management protocols. Genetic screening in specific populations could identify patients at risk, enabling preventive measures and reducing the burden of severe complications. Data comparing insulin infusion and plasmapheresis for treating HTG in HTG-AP-DKA is limited. Plasmapheresis may be more effective in LPL deficiency cases, warranting further research in the future. Presentation: Monday, July 14, 2025
2024-03-27 | Exchange Transfusion: A Good Option for the Acute Treatment of Familial Chylomicronemia Syndrome in the Neonatal Period
Familial chylomicronemia syndrome (FCS) is one of the rare causes of hypertriglyceridemia. Plasmapheresis is recommended in patients with triglyceride levels greater than 2000 mg/dL. However, plasmapheresis is difficult to perform in most centers due to technical inadequacies in the neonatal period. There are some reports in the literature on the efficacy of exchange transfusion. The index case involves a 20-day-old male patient who was admitted to the emergency department for restlessness and poor feeding. He was born at term with a birth weight of 4000 g. He was exclusively breastfed. The patient was taken to the neonatal intensive care unit due to his plasma being in the form of excessive lipemia. The first measurable triglyceride level was 5100 mg/dL (57.6 mmol/L). Breast milk was restricted, and intravenous hydration was started. However, his triglyceride level did not decrease despite this treatment. Other laboratory values could not be read due to excessive lipemic serum. On the third day of hospitalization, an exchange transfusion was decided upon in this case due to the development of respiratory distress (oxygen support, tachypnea). After exchange transfusion, the patient's triglyceride level reduced dramatically to 592 mg/dL (6.6 mmol/L), and his respiratory symptoms resolved. The aim of this case report is to demonstrate that exchange transfusion therapy is a safe and effective treatment modality in the neonatal period for the acute management of FCS. Furthermore, dietary therapy restricted to long-chain fatty acids combined with medium-chain fatty acid supplementation is highly effective in the chronic management of these patients.
small molecules
2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.
Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.
2026-04-23 | Severe hypertriglyceridemia due to lipoprotein lipase deficiency in an infant: pharmacological and nutritional approach.
This case describes the individualised pharmacological management of a 2-month-old infant with genetically confirmed type I hypertriglyceridemia due to lipoprotein lipase (LPL) deficiency. After the failure of conventional treatment and contraindication to plasmapheresis, intravenous insulin therapy was initiated, followed by subcutaneous insulin and omega-3 fatty acid adjustment. The hospital pharmacist played a key role in selecting off-label treatments, adapting pharmaceutical forms for paediatric use and performing therapeutic reconciliation. The approach was effective and safe, achieving triglyceride levels below 1000 mg/dL and clinical stability. This report contributes practical evidence on alternative treatment strategies for a rare disease with limited therapeutic options in paediatrics, highlighting the importance of a multidisciplinary approach and pharmaceutical care.
2025-12-03 | Long-term efficacy and safety of lomitapide in patients with familial chylomicronemia syndrome: Data from an expanded access program.
Familial chylomicronemia syndrome (FCS) is a rare, severe, autosomal recessive disorder characterized by extremely high triglyceride (TG) levels and an increased risk of acute and/or recurrent pancreatitis. Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, is approved for the treatment of homozygous familial hypercholesterolemia. The open-label, single-arm LOCHNES study (EudraCT 2018-002911-80) investigated lomitapide in adult patients with genetically confirmed FCS and a history of pancreatitis, demonstrating its efficacy and tolerability. Fourteen patients previously enrolled in the LOCHNES study were admitted to the Lomitapide Expanded Access Program 2 months after study completion. They were followed every 3 months over a nearly 3-year period (median follow-up: 33 months), continuing lomitapide at the maximum tolerated dose established during the trial. Evaluations included lipid profile, liver function tests, hepatic fat content, and liver stiffness. At the start of the follow-up period (after a 2-month lomitapide washout), median TG levels were 1899.5 mg/dL (range: 1013.5-2572 mg/dL). At the last observation, median fasting TGs were reduced to 376.5 mg/dL (range: 195-1328 mg/dL), representing a 80.2% decrease; 9 patients achieved TG levels ≤750 mg/dL. Adverse events were mostly mild-to-moderate, predominantly gastrointestinal (n = 11). Two patients experienced an episode of acute pancreatitis during follow-up. Liver enzymes ≥3 × the upper limit of normal were observed in 2 patients. Hepatic fat content increased in 3 patients, while median liver stiffness remained within the normal range. Lomitapide effectively and safely reduced TG levels in FCS patients with a history of pancreatitis over a nearly 3-year follow-up period. These findings are consistent with those of the open-label trial, despite the use of a lower median daily dose (27 mg). No new safety signals were observed.
2025-09-05 | The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications.
Cardiovascular disease remains a major global health challenge, with dyslipidaemia being a key modifiable risk factor. While low density lipoprotein cholesterol (LDL-C) is the primary target for lipid-lowering therapies, recent evidence highlights the importance of triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] for residual cardiovascular risk. Current lipid-lowering therapies target key enzymes and proteins involved in cholesterol and lipid metabolism. Statins inhibit HMG-CoA reductase, reducing cholesterol biosynthesis and increasing LDL receptor (LDLR) expression in the liver. Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate (MK0616)] prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption. Emerging lipid-lowering targets include angiopoietin-like 3 protein (ANGPTL3) and apolipoprotein C-III (apoC-III). Inhibiting ANGPTL3 reduces both triglycerides and LDL-C independently of LDL receptor. Inhibition of apoC-III unleashes lipoprotein lipase (LPL) activity, promoting triglyceride-rich particle catabolism, even in complete LPL deficiency. Cholesteryl ester transfer protein (CETP) inhibition also increases the catabolism of apoB-containing lipoproteins. Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities.
2025-06-12 | Lomitapide-induced fatty liver is a reversible condition: Evidence from a case of familial chylomicronemia syndrome.
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia. It is caused by loss-of-function variants in the genes encoding the lipoprotein lipase (LPL) enzyme and its cofactors, which severely impair the hydrolysis of triglycerides (TG). Its main complication is represented by acute pancreatitis (AP), a potentially life-threatening condition. Conventional TG-lowering therapies are poorly effective in FCS, thus requiring the search of novel treatments. Lomitapide, an inhibitor of microsomal triglyceride transfer protein (MTP), has demonstrated efficacy in reducing TG levels in FCS. However, it is associated with hepatic side effects, namely liver fat accumulation. Here we present a case study of a 71-year-old female patient with genetically confirmed FCS, baseline TG level of 2300 mg/dL (25.97 mmol/L) and a history of AP, who was treated with lomitapide for almost 5 years. The treatment allowed a marked reduction of TG (about 90%) and no recurrence of AP. However, hepatic monitoring during treatment revealed a progressive worsening of liver fat accumulation as detected by magnetic resonance imaging (MRI), which was associated with pronounced increases in liver transaminases and liver stiffness (up to 15 kPa). Due to these hepatic adverse events, it was decided to discontinue therapy with lomitapide. An MRI scan repeated after 70 days of drug withdrawal revealed complete resolution of fatty liver disease associated with normalization of liver stiffness (4.1 kPa) and liver transaminases. This case demonstrates the reversibility of lomitapide-induced fatty liver and underscores the importance of regular monitoring of the liver safety during lomitapide to guide timely interventions.
proteins
2026-09-10 | Clinical and functional evidence supporting pathogenicity of a novel APOA5 variant in familial chylomicronemia syndrome.
This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
2026-05-21 | Functional characterization of furin-mediated lipoprotein lipase cleavage.
Lipoprotein lipase (LPL) is the rate-limiting enzyme that hydrolyzes triglycerides within circulating lipoproteins. LPL dysfunction leads to familial LPL deficiency, which is characterized by chylomicronemia and high risk for acute pancreatitis. Although cell culture studies indicate that the protease furin inactivates LPL by cleavage, the physiological relevance of this process remains unclear. In this study, we investigated the impact of furin-mediated LPL cleavage in vivo using inducible knockout mouse models and gene therapy. After identifying the tissue-specific prevalence of LPL cleavage, we compared mice expressing a furin-resistant LPL mutant versus furin-sensitive LPL. Our results demonstrate that furin-resistant LPL lowers longitudinal plasma triglyceride levels without causing adverse effects, such as hepatic steatosis. These findings highlight that engineered furin resistance is a viable strategy to enhance the metabolic function of LPL.
2026-03-20 | The evaluation of plozasiran for the treatment of familial chylomicronemia syndrome.
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder marked by severe hypertriglyceridemia and characteristic clinical manifestations, particularly acute pancreatitis. Conventional triglyceride-lowering therapy is largely ineffective. Apolipoprotein (apo) C-III has emerged as a key therapeutic target to lower triglycerides in FCS. This review compares FCS with more common multifactorial chylomicronemia. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'plozasiran,' 'olezarsen,' and 'volanesorsen.' We outline traditional management strategies and their limited role in FCS and explore non-traditional therapies including orlistat, lomitapide, inhibitors of angiopoietin like protein 3 (ANGPTL3), and analogues of fibroblast growth factor 21 (FGF21). The primary focus is on RNA-based gene silencing therapeutics that target apo C-III, particularly the small interfering RNA plozasiran and the allele specific oligonucleotides volanesorsen and olezarsen, highlighting key differences in efficacy and tolerability. In a phase 3 trial of plozasiran, at 10 months, median placebo-adjusted reductions in apo C-III were approximately -90%, while TG levels were reduced up to -59%. Thus, plozasiran and alternative RNA-based therapeutics directed against APOC3 represent transformational therapies for patients with FCS and related phenotypes characterized by severe recalcitrant hypertriglyceridemia.
2025-11-27 | Genetic Assessment and Clinical Correlates in Severe Hypertriglyceridemia: A Systematic Review.
Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed scientific literature up to 2025 for studies reporting genetic data, clinical features, or therapeutic outcomes in adults with triglycerides (TG) ≥ 500 mg/dL. Extracted data were synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, and treatment response. Results: Ten studies (n = 2521) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for <5% of cases and showed extreme TG elevations (>2800 mg/dL) with pancreatitis prevalence (>70%). APOA5, APOC3, and APOB variants were associated with intermediate TG levels and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). Polygenic hypertriglyceridemia represented ~70-80% of cases, with TG ≈ 2200 mg/dL and pancreatitis prevalence 15-20%, largely modulated by metabolic triggers. MASLD was present in >70% of polygenic cases, supporting a "two-hit" model where hepatic overproduction of TG-rich lipoproteins amplifies TG excess. Interventional trials demonstrated TG reductions with APOC3 antisense therapy (70-80%) and ANGPTL3 inhibition (50-55%), while GLP-1RA significantly reduced hepatic fat (30-35%) and resolved NASH in up to 59% of patients. Conclusions: SHTG displays a genotype-phenotype gradient: FCS is linked to recurrent pancreatitis, whereas polygenic/MCS forms are closely associated with MASLD and metabolic dysfunction. These findings support a precision-medicine approach integrating genetic testing and PRS-guided strategies-prioritizing APOC3/ANGPTL3 inhibitors for FCS and combined TG-lowering plus metabolic therapies for MCS-to reduce pancreatitis recurrence and liver disease.
2025-07-25 | Effect of olezarsen on lipoprotein-associated ApoC-III levels in patients with familial chylomicronemia syndrome.
Apolipoprotein C-III (apoC-III) is transported on chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein(a) [Lp(a)]. Olezarsen, a hepatic-targeted antisense oligonucleotide targeting APOC3 mRNA, lowers apoC-III and triglycerides and reduces pancreatitis events. This study evaluated the reduction of apoC-III in specific lipoprotein pools after treatment with olezarsen. Participants with familial chylomicronemia syndrome (FCS) in the Balance study received olezarsen 80 mg (n = 22), 50 mg (n = 21), or placebo (n = 23). Triglycerides, apoC-III, and lipoprotein-associated apoC-III was measured at baseline and days 85, 169, 253, and 365 using chemiluminescent ELISAs. Lipoprotein-associated apoC-III levels were measured in 4 lipoprotein pools, apoC-III-total apoB (apoB-48+apoB-100), apoC-III-apoA-I (HDL), apoC-III-apoB-100 (VLDL + LDL), and apoC-III-apo(a) (Lp(a)). The placebo-adjusted average percent changes from baseline to day 365 were calculated. The average percent changes from baseline to day 365 in apoC-III were -61.9 % and -74.7 % and for triglycerides -37.8 % and -55.7 % with olezarsen 50 mg and olezarsen 80 mg, respectively. The corresponding olezarsen-placebo average differences (95 % CI) in apoC-III-total apoB levels were -47.1 % (-64.1, -32.6) and -65.8 % (-81.5, -49.8), respectively and apoC-III-apoA-I by -53.6 % (-79.3, -29.4) and -76.1 % (-104.1, -55.4), respectively (p<0.001 for all). ApoC-III-apoB-100 was reduced by -12.5 % (-28.1, 2.1) (p = 0.0768) and -29.9 % (-46.1, -16.0) (p = 0.0006) and apoC-III-apo(a) by -15.7 % (-47.5, 10.6) (p = 0.18) and -39.1 % (-70.2, -16.1) (p = 0.0024), with olezarsen 50 mg and olezarsen 80 mg respectively. In adults with FCS, olezarsen significantly lowers apoC-III in all major lipoprotein pools, particularly in total apoB and apoA-I. Tracking changes in apoC-III among various lipoprotein pools elucidates the action of olezarsen on apoC-III and may inform future studies of pancreatitis and cardiovascular risk with apoC-III-targeted therapies.
oligonucleotides
2026-08-19 | Plozasiran: a small interfering RNA therapy for hypertriglyceridemia and familial chylomicronemia syndrome.
Plozasiran (Redemplo®) is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. It degrades ApoC-III mRNA and results in reduced levels of hepatic and serum ApoC-III protein, which leads to an increased clearance of serum triglycerides. In the phase 3 PALISADE trial, plozasiran 25 mg reduced fasting triglyceride levels by approximately 80% at 10 months in patients with familial chylomicronemia syndrome (FCS) and was associated with a lower incidence of pancreatitis compared with placebo. This provides supportive, yet not definitive, evidence for pancreatitis prevention as the PALISADE trial was powered to investigate triglyceride lowering. Across completed clinical studies, plozasiran demonstrated a generally favorable safety profile, with a low incidence of thrombocytopenia and adverse events primarily limited to abdominal pain, nasopharyngitis, headache, and nausea. Hyperglycemia was observed in some patients with preexisting diabetes or prediabetes at baseline. Ongoing phase 3 trials (SHASTA-3, SHASTA-4, SHASTA-5, SHASTA-10, MUIR-3 and CAPITAN) are further evaluating the efficacy and safety of plozasiran in broader populations with hypertriglyceridemia, including its potential role in reducing cardiovascular risk and preventing pancreatitis. Compared with earlier ApoC-III-targeted antisense oligonucleotides, plozasiran offers the advantages of less frequent dosing, sustained pharmacodynamic effects, and potentially a more favorable tolerability profile based on indirect evidence, positioning it as a promising therapeutic option for patients with FCS and other severe hypertriglyceridemia disorders inadequately managed with existing therapies.
2026-07-23 | Familial Chylomicronemia Syndrome Due to a Homozygous LPL c.644G>A Variant and Response to Volanesorsen in Colombia: A Case Report.
Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by persistent severe hypertriglyceridemia and recurrent acute pancreatitis, and is frequently misdiagnosed as multifactorial hypertriglyceridemia. We report the case of a 57-year-old Colombian male with recurrent acute pancreatitis and severe hypertriglyceridemia peaking at 4,350 mg/dL, refractory to fibrates, statins, and omega-3 fatty acids, with persistently low low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels. Secondary causes were excluded, and chronic valproic acid therapy was identified as a potential aggravating factor. A Moulin score of 10 points classified FCS as highly probable, and next-generation sequencing confirmed a homozygous pathogenic LPL variant, NM_000237.3.644G>A, p.(Gly215Glu), associated with loss of enzymatic activity. Following diagnostic confirmation, volanesorsen produced a sustained triglyceride reduction, with no new episodes of pancreatitis during uninterrupted therapy. This case underscores the importance of suspecting FCS in patients with refractory severe hypertriglyceridemia and recurrent pancreatitis. Molecular diagnosis enables access to precision medicine-based strategies with a meaningful impact on clinical outcomes and quality of life.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
2026-05-26 | Comparative efficacy and safety of olezarsen vs plozasiran for familial chylomicronemia syndrome: A matching-adjusted indirect comparison.
Familial chylomicronemia syndrome (FCS) is a rare genetic form of primary hypertriglyceridemia with an increased risk of acute pancreatitis (AP). Apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran, provide therapeutic approaches to reduce triglycerides in patients with FCS. To compare the efficacy and safety of olezarsen (Balance) with plozasiran (PALISADE) in FCS. An anchored matching-adjusted indirect comparison was conducted. Outcome analyses included only the approved dosages of study therapies, while the AP analysis also pooled high- and low-dose regimens. Analyses showed no statistically significant differences in 52-week efficacy or safety. Mean differences (olezarsen vs plozasiran) in triglycerides and apoC-III reduction were -15.5% (95% CI: -76.2, 45.2) and -8.4% (95% CI: -69.7, 53.0). Relative risks of AP, treatment-emergent, and serious adverse events were 0.70 (95% CI: 0.07, 6.66), 0.81 (95% CI: 0.58, 1.13), and 0.50 (95% CI: 0.10, 2.58). Overall, there was no evidence of differences in efficacy or safety between olezarsen and plozasiran in the treatment of patients with FCS.
2026-04-21 | Clinical identification of familial chylomicronemia syndrome and novel therapeutic options.
Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder driven by both genetic susceptibility and secondary factors. Most patients with severe HTG (triglyceride [TG] >10 mmol/L [>885 mg/dL]) have multifactorial chylomicronemia syndrome (MCS) while only a few have familial chylomicronemia syndrome (FCS), a rare autosomal recessive condition. We summarize the pathophysiology of severe HTG, emphasizing impaired intravascular lipolysis of TG-rich lipoproteins and the regulatory role of apolipoproteins (apo), particularly apo C-III. We outline features that distinguish FCS from MCS and discuss diagnostic strategies, including clinical scoring systems and targeted genetic testing. Current management approaches, including responses to conventional TG-lowering therapies and emerging biologic therapies targeting apo C-III, are examined. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'familial chylomicronemia syndrome,' 'multifactorial chylomicronemia syndrome,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'antisense oligonucleotides,' and 'apolipoprotein C-III.' Differentiating FCS from MCS is critical because RNA-based inhibition of apo C-III has transformed the therapeutic landscape for FCS patients. These agents provide substantial, durable TG lowering, and meaningful reductions in pancreatitis risk, although cardiovascular benefit remains uncertain. Future efforts should focus on optimizing diagnostic pathways, assessing cardiovascular outcomes, and determining long-term safety of these novel biologic therapies.
other
2026-06-17 | Heterozygosity for pathogenic variants in familial chylomicronemia syndrome genes: from carrier state to complex trait.
Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
2026-05-01 | Abstract Fri027: Apob18, An Inhibitor Of Endothelial Cell Lipoprotein Uptake, Reduces Vascular Inflammation
Hypertriglyceridemia is increasingly recognized as a key driver of endothelial activation and atherosclerosis. We recently reported that hypertriglyceridemia caused by induced global lipoprotein lipase-deficiency ( iLpl -/- ) trigger endothelial inflammatory signatures and accelerated aortic plaque development in LDL receptor knockout ( Ldlr -/- ) mice, underscoring the pathogenic role of nascent triglyceride (TG)-rich lipoproteins (TRLs) in vascular disease. We also showed that a protein fragment comprising the N-terminal 18% of apolipoprotein B100 (ApoB18) blocks endothelial cell uptake of chylomicrons. In this study, we investigated the effects of liver-targeted adeno-associated virus (AAV)-mediated expression of ApoB18 (TBG-AAV8-ApoB18) on vascular inflammation in Ldlr -/- and iLpl -/- /Ldlr -/- mice following 12 weeks of Western diet feeding. An empty TBG-AAV8 was used as control. Compared with Ldlr -/- mice, iLpl -/- /Ldlr -/- mice exhibited markedly elevated circulating TG levels (1193 mg/dL vs. 264 mg/dL; n=14). Single-cell RNA-sequencing of the aorta (n=4) revealed robust upregulation of inflammatory genes, including Thbs1, Vcam1, Icam1, Tgfb1, Nfkb1, Klf2, and Klf4 in endothelial cells, macrophages, and smooth muscle cells, indicating widespread vascular inflammation in iLpl -/- /Ldlr -/- mice compared with Ldlr -/- mice. Pathway enrichment analysis further demonstrated that global LPL-deficiency elevated multiple pro-atherogenic and inflammatory signaling networks, including lipid and atherosclerosis pathways as well as MAPK signaling, consistent with an enhanced cellular response to dysregulated lipid metabolism. TBG-AAV8-ApoB18 treatment attenuated the expression of these inflammatory genes in both genotypes. Assessment of circulating ApoB18 showed that this protein was expressed at a molar ratio of less than 10% of both lipoprotein ApoB100 and ApoB48 and in vitro competition studies confirmed that this fragment appeared to be a better ligand for both scavenger receptor BI and activin-like kinase 1 than lipoprotein-associated ApoB , since competition with ApoB18 at a molar ratio as low as 1% significantly inhibited EC uptake of both LDL (48.2% uptake compared to control, p<0.0001) and chylomicrons (42.3% uptake compared to control, p<0.0001). These findings demonstrate that AAV-mediated ApoB18 expression attenuates vascular inflammation, with likely implications for atherosclerosis enhanced by endothelial cell uptake of ApoB-containing lipoproteins.
2025-11-15 | An Updated Review of Novel Triglyceride-Lowering Therapies in Adults with Familial Chylomicronemia Syndrome.
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder resulting in hypertriglyceridemia. Historically, treatment options for this patient population have been limited as available triglyceride-lowering medications are often ineffective. Recently, new pharmacological agents targeting apolipoprotein C-III (apoC-III) production have been found to effectively and substantially lower triglyceride levels. A literature search in PubMed and EMBASE was conducted from January 2013 to July 2025 using keywords "familial chylomicronemia syndrome", "olezarsen", "volanesorsen", and "plozasiran". Phase III trials evaluating safety and efficacy of volanesorsen, olezarsen, and plozasiran were included. From 1376 articles, 4 phase III trials fulfilled the inclusion criteria. Triglyceride (TG) levels were reduced by 73-77% with volanesorsen, a least-square means reduction in TGs between 22.4 and 43.5 percentage points with olezarsen, and a 78-80% reduction in TGs with plozasiran when compared with placebo. The number of acute pancreatitis events was also lower with the study medications versus placebo. These new apoC-III lowering medications provide a novel treatment approach for patients with FCS, a population long without effective pharmacological treatment options. Provider familiarity with the availability and purpose of these medications will allow patients to receive the best therapy available to manage FCS.
2025-03-27 | Optimization of adeno-associated viral (AAV) gene therapies vectors for balancing efficacy, longevity and safety for clinical application.
Adeno-associated viral (AAV) vectors are an ideal platform for gene therapy due to their ability to deliver therapeutic cargos safely and effectively across various target organs. Their low immunogenicity contributes to long-lasting therapeutic effects. However, recent insights highlight the significance of CpG content within AAV vectors, where unmethylated CpG dinucleotides can trigger a TLR9-mediated immune response, leading to the rapid elimination of transduced cells. Clinical evidence indicates an inverse relationship between CpG content and therapeutic success, with lower CpG counts correlating with sustained transgene expression. Here, we sought to optimize a novel, CpG-rich AAV8 vector, referred to as pVR59, designed for treating lipoprotein lipase deficiency (LPLD). We strategically reduced CpG levels in pVR59, resulting in the development of pNC182, a CpG-depleted vector that maintains therapeutic efficacy. A single intramuscular injection of pNC182 demonstrated comparable effectiveness to pVR59 in normalizing lipemia and hypertriglyceridemia in LPLD mouse models, with a 38% reduction in total CpG count. These findings support the clinical application of pNC182 as a safe, long-lasting AAV gene therapy for LPLD and provide a framework for future AAV vector designs aimed at maximizing therapeutic efficacy while minimizing immunogenic responses in human settings.
2025-03-06 | Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia.
Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability. To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab. A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients. After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L). The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).
cell therapies
2026-07-14 | Lipoprotein lipase deficiency presenting with gastrointestinal bleeding and compensated shock.
Lipoprotein lipase (LPL) deficiency is an autosomal recessive disorder causing hypertriglyceridemia. Presentations are heterogenous and there are no standardized acute treatment protocols. Long-term management consists of strict dietary control. We report a case of LPL deficiency in an infant presenting with gastrointestinal bleeding and compensated shock, with a more severe presentation than previously published cases. Preliminary diagnosis was based on lipemic blood appearance. Intensive care resuscitation was required. Triglyceride levels peaked above 200 times the upper limit of normal. Insulin infusion provided no benefit. A whole-blood exchange transfusion led to a sustained reduction in triglyceride levels. Diagnosis was confirmed by genetic testing. Despite the magnitude of hypertriglyceridemia, there were minimal end-organ sequelae. The necessity of invasive management of severe hypertriglyceridemia is not established. This case highlights the range of presentations in inherited metabolic disease, and the limited evidence for acute management strategies.
2026-04-02 | Therapeutic plasmapheresis in a young infant with severe hypertriglyceridemia: a case report.
Familial lipoprotein lipase (LPL) deficiency typically occurs during childhood and is characterized by severe hypertriglyceridemia, accompanied by episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. The clearance of chylomicrons from plasma is impaired, causing triglyceride accumulation and giving the plasma a milky/lactescent/lipemic appearance. Symptoms typically resolve when total dietary fat is restricted to 20 g/d. Acute management focuses on maintaining triglyceride levels using insulin, plasmapheresis, blood exchange transfusion, and heparin, although few of these interventions have proven effective in infants. Here, we report a rare case of severe hypertriglyceridemia in a 40-d-old infant who presented with respiratory distress, xanthoma, hepatosplenomegaly, and lipemic samples. Plasmapheresis resulted in a reduction in triglyceride levels and clinical improvement, and further evaluation confirmed a diagnosis of LPL deficiency. Familial LPL deficiency can occur during early infancy, with life-threatening complications. A consensus on the acute management of hypertriglyceridemia in the pediatric population needs to be meticulously established after exploring possible treatment strategies, including plasmapheresis.
2026-01-01 | Sequential Continuous Renal Replacement Therapy and Therapeutic Plasma Exchange in Pediatric Necrotizing Hypertriglyceridemia-Induced Pancreatitis with Suspected Familial Chylomicronemia Syndrome: A Case Report
Background: Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is a severe and underrecognized etiology of pancreatitis, accounting for 1% - 4% of all cases in adults, with extreme triglyceridemia raising the risk of fulminant multi-organ failure. When underlying lipoprotein lipase (LPL) deficiency is suspected—as in familial chylomicronemia syndrome (FCS)—conventional pharmacologic strategies are inherently limited, and therapeutic plasma exchange (TPE) represents the most effective currently available approach for the rapid removal of chylomicrons and triglyceride-rich lipoproteins from the circulation. Case Summary: We report a 14-year-old girl presenting with triglycerides > 14,000 mg/dL, severe necrotizing pancreatitis, acute kidney injury (AKI), mild acute respiratory distress syndrome (ARDS), and metabolic encephalopathy. No prior medical history was identified. Despite aggressive pharmacologic therapy with intravenous insulin, heparin, and fibrates, triglyceride levels remained critically elevated. Continuous renal replacement therapy (CRRT) was initiated for AKI, metabolic acidosis, and hemodynamic instability, achieving significant physiologic stabilization. However, because CRRT does not effectively clear chylomicrons, lipid levels remained dangerously high. Two urgent sessions of TPE reduced triglycerides from >14,000 mg/dL to approximately 300 mg/dL, with subsequent normalization of pancreatic enzymes and full recovery of renal, respiratory, and neurological function. The patient was discharged in good clinical condition. Conclusion: This case illustrates that CRRT and TPE fulfill distinct, non-overlapping roles in severe HTG-AP. CRRT provides essential metabolic bridge support, and TPE achieves definitive lipid clearance. When LPL deficiency is suspected, early escalation to TPE is potentially lifesaving. A high index of clinical suspicion and timely decision-making are the key determinants of outcome in this rare but catastrophic condition.
2025-10-01 | MON-658 When Metabolic Stress Meets Genetics: A Triad of DKA, Acute Pancreatitis, and Hypertriglyceridemia in a Patient with LMF1 Mutation
Abstract Disclosure: S. Abou Khachfe: None. C. Guillen-Lopez: None. A. Patel: None. M. Lonescu: None. Introduction: The combination of diabetic ketoacidosis (DKA), severe hypertriglyceridemia (HTG), and acute pancreatitis (AP) is a rare but critical triad with mortality rates up to 80%. It presents diagnostic and management challenges, often causing metabolic disturbances, organ failure, and prolonged stays. The pathophysiology of this triad is complex, with evidence suggesting a bidirectional relationship. HTG seems to link DKA and AP, though the directionality (DKA→HTG→AP vs. HTG→AP→DKA) remains unclear. In DKA, insulin deficiency promotes lipolysis, increasing free fatty acids (FFA) and very low-density lipoprotein (VLDL) production in the liver, leading to HTG. While moderate HTG is common in DKA, severe HTG (triglycerides >1,000 mg/dL) is rare. In such cases, underlying genetic mutations should be considered. The lipase maturation factor (LMF1) gene encodes a protein essential for lipoprotein lipase (LPL) function, which breaks down triglycerides in chylomicrons and VLDL. Mutations in LMF1 disrupt this process, resulting in severe HTG. Case: A 30-year-old male with poorly controlled T2DM, HTG, and recurrent pancreatitis presented with severe abdominal pain. He had poor adherence to metformin, Jardiance, and pioglitazone, with an A1C of 10.7%. Labs showed lipase 1611 U/L, glucose 238 mg/dL, anion gap 27, beta-hydroxybutyrate 9.7 mmol/L, and triglycerides >2000 mg/dL. He was admitted and treated with IV hydration, insulin infusion, statins, and fenofibrate for euglycemic DKA and HTG-induced AP. Persistently elevated triglycerides >1000 mg/dL required two plasmapheresis sessions, leading to clinical improvement. He was discharged on insulin, atorvastatin, and fenofibrate with a diabetes education referral. Given his recurrent HTG-AP-DKA (>5 episodes), genetic testing for primary HTG was performed, revealing a heterozygous missense mutation in the LMF1 gene (c.1352G>A, p.Arg451Gln). Discussion: AP and DKA are life-threatening conditions with mortality rates reaching 80% when they coexist. Overlapping symptoms and nonspecific amylase and lipase elevations in DKA can complicate diagnosis, leading to poor outcomes. Multidisciplinary collaboration and increased physician awareness are key for optimal management. Current AP severity scoring systems, like Ranson and APACHE II, are impacted by DKA-related factors such as high glucose and low pH, making them less reliable in these cases, highlighting the need for tailored scoring systems, more effective diagnostic algorithms, and specific management protocols. Genetic screening in specific populations could identify patients at risk, enabling preventive measures and reducing the burden of severe complications. Data comparing insulin infusion and plasmapheresis for treating HTG in HTG-AP-DKA is limited. Plasmapheresis may be more effective in LPL deficiency cases, warranting further research in the future. Presentation: Monday, July 14, 2025
2024-03-27 | Exchange Transfusion: A Good Option for the Acute Treatment of Familial Chylomicronemia Syndrome in the Neonatal Period
Familial chylomicronemia syndrome (FCS) is one of the rare causes of hypertriglyceridemia. Plasmapheresis is recommended in patients with triglyceride levels greater than 2000 mg/dL. However, plasmapheresis is difficult to perform in most centers due to technical inadequacies in the neonatal period. There are some reports in the literature on the efficacy of exchange transfusion. The index case involves a 20-day-old male patient who was admitted to the emergency department for restlessness and poor feeding. He was born at term with a birth weight of 4000 g. He was exclusively breastfed. The patient was taken to the neonatal intensive care unit due to his plasma being in the form of excessive lipemia. The first measurable triglyceride level was 5100 mg/dL (57.6 mmol/L). Breast milk was restricted, and intravenous hydration was started. However, his triglyceride level did not decrease despite this treatment. Other laboratory values could not be read due to excessive lipemic serum. On the third day of hospitalization, an exchange transfusion was decided upon in this case due to the development of respiratory distress (oxygen support, tachypnea). After exchange transfusion, the patient's triglyceride level reduced dramatically to 592 mg/dL (6.6 mmol/L), and his respiratory symptoms resolved. The aim of this case report is to demonstrate that exchange transfusion therapy is a safe and effective treatment modality in the neonatal period for the acute management of FCS. Furthermore, dietary therapy restricted to long-chain fatty acids combined with medium-chain fatty acid supplementation is highly effective in the chronic management of these patients.
small molecules
2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.
Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.
2026-04-23 | Severe hypertriglyceridemia due to lipoprotein lipase deficiency in an infant: pharmacological and nutritional approach.
This case describes the individualised pharmacological management of a 2-month-old infant with genetically confirmed type I hypertriglyceridemia due to lipoprotein lipase (LPL) deficiency. After the failure of conventional treatment and contraindication to plasmapheresis, intravenous insulin therapy was initiated, followed by subcutaneous insulin and omega-3 fatty acid adjustment. The hospital pharmacist played a key role in selecting off-label treatments, adapting pharmaceutical forms for paediatric use and performing therapeutic reconciliation. The approach was effective and safe, achieving triglyceride levels below 1000 mg/dL and clinical stability. This report contributes practical evidence on alternative treatment strategies for a rare disease with limited therapeutic options in paediatrics, highlighting the importance of a multidisciplinary approach and pharmaceutical care.
2025-12-03 | Long-term efficacy and safety of lomitapide in patients with familial chylomicronemia syndrome: Data from an expanded access program.
Familial chylomicronemia syndrome (FCS) is a rare, severe, autosomal recessive disorder characterized by extremely high triglyceride (TG) levels and an increased risk of acute and/or recurrent pancreatitis. Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, is approved for the treatment of homozygous familial hypercholesterolemia. The open-label, single-arm LOCHNES study (EudraCT 2018-002911-80) investigated lomitapide in adult patients with genetically confirmed FCS and a history of pancreatitis, demonstrating its efficacy and tolerability. Fourteen patients previously enrolled in the LOCHNES study were admitted to the Lomitapide Expanded Access Program 2 months after study completion. They were followed every 3 months over a nearly 3-year period (median follow-up: 33 months), continuing lomitapide at the maximum tolerated dose established during the trial. Evaluations included lipid profile, liver function tests, hepatic fat content, and liver stiffness. At the start of the follow-up period (after a 2-month lomitapide washout), median TG levels were 1899.5 mg/dL (range: 1013.5-2572 mg/dL). At the last observation, median fasting TGs were reduced to 376.5 mg/dL (range: 195-1328 mg/dL), representing a 80.2% decrease; 9 patients achieved TG levels ≤750 mg/dL. Adverse events were mostly mild-to-moderate, predominantly gastrointestinal (n = 11). Two patients experienced an episode of acute pancreatitis during follow-up. Liver enzymes ≥3 × the upper limit of normal were observed in 2 patients. Hepatic fat content increased in 3 patients, while median liver stiffness remained within the normal range. Lomitapide effectively and safely reduced TG levels in FCS patients with a history of pancreatitis over a nearly 3-year follow-up period. These findings are consistent with those of the open-label trial, despite the use of a lower median daily dose (27 mg). No new safety signals were observed.
2025-09-05 | The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications.
Cardiovascular disease remains a major global health challenge, with dyslipidaemia being a key modifiable risk factor. While low density lipoprotein cholesterol (LDL-C) is the primary target for lipid-lowering therapies, recent evidence highlights the importance of triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] for residual cardiovascular risk. Current lipid-lowering therapies target key enzymes and proteins involved in cholesterol and lipid metabolism. Statins inhibit HMG-CoA reductase, reducing cholesterol biosynthesis and increasing LDL receptor (LDLR) expression in the liver. Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate (MK0616)] prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption. Emerging lipid-lowering targets include angiopoietin-like 3 protein (ANGPTL3) and apolipoprotein C-III (apoC-III). Inhibiting ANGPTL3 reduces both triglycerides and LDL-C independently of LDL receptor. Inhibition of apoC-III unleashes lipoprotein lipase (LPL) activity, promoting triglyceride-rich particle catabolism, even in complete LPL deficiency. Cholesteryl ester transfer protein (CETP) inhibition also increases the catabolism of apoB-containing lipoproteins. Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities.
2025-06-12 | Lomitapide-induced fatty liver is a reversible condition: Evidence from a case of familial chylomicronemia syndrome.
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia. It is caused by loss-of-function variants in the genes encoding the lipoprotein lipase (LPL) enzyme and its cofactors, which severely impair the hydrolysis of triglycerides (TG). Its main complication is represented by acute pancreatitis (AP), a potentially life-threatening condition. Conventional TG-lowering therapies are poorly effective in FCS, thus requiring the search of novel treatments. Lomitapide, an inhibitor of microsomal triglyceride transfer protein (MTP), has demonstrated efficacy in reducing TG levels in FCS. However, it is associated with hepatic side effects, namely liver fat accumulation. Here we present a case study of a 71-year-old female patient with genetically confirmed FCS, baseline TG level of 2300 mg/dL (25.97 mmol/L) and a history of AP, who was treated with lomitapide for almost 5 years. The treatment allowed a marked reduction of TG (about 90%) and no recurrence of AP. However, hepatic monitoring during treatment revealed a progressive worsening of liver fat accumulation as detected by magnetic resonance imaging (MRI), which was associated with pronounced increases in liver transaminases and liver stiffness (up to 15 kPa). Due to these hepatic adverse events, it was decided to discontinue therapy with lomitapide. An MRI scan repeated after 70 days of drug withdrawal revealed complete resolution of fatty liver disease associated with normalization of liver stiffness (4.1 kPa) and liver transaminases. This case demonstrates the reversibility of lomitapide-induced fatty liver and underscores the importance of regular monitoring of the liver safety during lomitapide to guide timely interventions.
proteins
2026-09-10 | Clinical and functional evidence supporting pathogenicity of a novel APOA5 variant in familial chylomicronemia syndrome.
This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
2026-05-21 | Functional characterization of furin-mediated lipoprotein lipase cleavage.
Lipoprotein lipase (LPL) is the rate-limiting enzyme that hydrolyzes triglycerides within circulating lipoproteins. LPL dysfunction leads to familial LPL deficiency, which is characterized by chylomicronemia and high risk for acute pancreatitis. Although cell culture studies indicate that the protease furin inactivates LPL by cleavage, the physiological relevance of this process remains unclear. In this study, we investigated the impact of furin-mediated LPL cleavage in vivo using inducible knockout mouse models and gene therapy. After identifying the tissue-specific prevalence of LPL cleavage, we compared mice expressing a furin-resistant LPL mutant versus furin-sensitive LPL. Our results demonstrate that furin-resistant LPL lowers longitudinal plasma triglyceride levels without causing adverse effects, such as hepatic steatosis. These findings highlight that engineered furin resistance is a viable strategy to enhance the metabolic function of LPL.
2026-03-20 | The evaluation of plozasiran for the treatment of familial chylomicronemia syndrome.
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder marked by severe hypertriglyceridemia and characteristic clinical manifestations, particularly acute pancreatitis. Conventional triglyceride-lowering therapy is largely ineffective. Apolipoprotein (apo) C-III has emerged as a key therapeutic target to lower triglycerides in FCS. This review compares FCS with more common multifactorial chylomicronemia. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'plozasiran,' 'olezarsen,' and 'volanesorsen.' We outline traditional management strategies and their limited role in FCS and explore non-traditional therapies including orlistat, lomitapide, inhibitors of angiopoietin like protein 3 (ANGPTL3), and analogues of fibroblast growth factor 21 (FGF21). The primary focus is on RNA-based gene silencing therapeutics that target apo C-III, particularly the small interfering RNA plozasiran and the allele specific oligonucleotides volanesorsen and olezarsen, highlighting key differences in efficacy and tolerability. In a phase 3 trial of plozasiran, at 10 months, median placebo-adjusted reductions in apo C-III were approximately -90%, while TG levels were reduced up to -59%. Thus, plozasiran and alternative RNA-based therapeutics directed against APOC3 represent transformational therapies for patients with FCS and related phenotypes characterized by severe recalcitrant hypertriglyceridemia.
2025-11-27 | Genetic Assessment and Clinical Correlates in Severe Hypertriglyceridemia: A Systematic Review.
Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed scientific literature up to 2025 for studies reporting genetic data, clinical features, or therapeutic outcomes in adults with triglycerides (TG) ≥ 500 mg/dL. Extracted data were synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, and treatment response. Results: Ten studies (n = 2521) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for <5% of cases and showed extreme TG elevations (>2800 mg/dL) with pancreatitis prevalence (>70%). APOA5, APOC3, and APOB variants were associated with intermediate TG levels and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). Polygenic hypertriglyceridemia represented ~70-80% of cases, with TG ≈ 2200 mg/dL and pancreatitis prevalence 15-20%, largely modulated by metabolic triggers. MASLD was present in >70% of polygenic cases, supporting a "two-hit" model where hepatic overproduction of TG-rich lipoproteins amplifies TG excess. Interventional trials demonstrated TG reductions with APOC3 antisense therapy (70-80%) and ANGPTL3 inhibition (50-55%), while GLP-1RA significantly reduced hepatic fat (30-35%) and resolved NASH in up to 59% of patients. Conclusions: SHTG displays a genotype-phenotype gradient: FCS is linked to recurrent pancreatitis, whereas polygenic/MCS forms are closely associated with MASLD and metabolic dysfunction. These findings support a precision-medicine approach integrating genetic testing and PRS-guided strategies-prioritizing APOC3/ANGPTL3 inhibitors for FCS and combined TG-lowering plus metabolic therapies for MCS-to reduce pancreatitis recurrence and liver disease.
2025-07-25 | Effect of olezarsen on lipoprotein-associated ApoC-III levels in patients with familial chylomicronemia syndrome.
Apolipoprotein C-III (apoC-III) is transported on chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein(a) [Lp(a)]. Olezarsen, a hepatic-targeted antisense oligonucleotide targeting APOC3 mRNA, lowers apoC-III and triglycerides and reduces pancreatitis events. This study evaluated the reduction of apoC-III in specific lipoprotein pools after treatment with olezarsen. Participants with familial chylomicronemia syndrome (FCS) in the Balance study received olezarsen 80 mg (n = 22), 50 mg (n = 21), or placebo (n = 23). Triglycerides, apoC-III, and lipoprotein-associated apoC-III was measured at baseline and days 85, 169, 253, and 365 using chemiluminescent ELISAs. Lipoprotein-associated apoC-III levels were measured in 4 lipoprotein pools, apoC-III-total apoB (apoB-48+apoB-100), apoC-III-apoA-I (HDL), apoC-III-apoB-100 (VLDL + LDL), and apoC-III-apo(a) (Lp(a)). The placebo-adjusted average percent changes from baseline to day 365 were calculated. The average percent changes from baseline to day 365 in apoC-III were -61.9 % and -74.7 % and for triglycerides -37.8 % and -55.7 % with olezarsen 50 mg and olezarsen 80 mg, respectively. The corresponding olezarsen-placebo average differences (95 % CI) in apoC-III-total apoB levels were -47.1 % (-64.1, -32.6) and -65.8 % (-81.5, -49.8), respectively and apoC-III-apoA-I by -53.6 % (-79.3, -29.4) and -76.1 % (-104.1, -55.4), respectively (p<0.001 for all). ApoC-III-apoB-100 was reduced by -12.5 % (-28.1, 2.1) (p = 0.0768) and -29.9 % (-46.1, -16.0) (p = 0.0006) and apoC-III-apo(a) by -15.7 % (-47.5, 10.6) (p = 0.18) and -39.1 % (-70.2, -16.1) (p = 0.0024), with olezarsen 50 mg and olezarsen 80 mg respectively. In adults with FCS, olezarsen significantly lowers apoC-III in all major lipoprotein pools, particularly in total apoB and apoA-I. Tracking changes in apoC-III among various lipoprotein pools elucidates the action of olezarsen on apoC-III and may inform future studies of pancreatitis and cardiovascular risk with apoC-III-targeted therapies.
oligonucleotides
2026-08-19 | Plozasiran: a small interfering RNA therapy for hypertriglyceridemia and familial chylomicronemia syndrome.
Plozasiran (Redemplo®) is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. It degrades ApoC-III mRNA and results in reduced levels of hepatic and serum ApoC-III protein, which leads to an increased clearance of serum triglycerides. In the phase 3 PALISADE trial, plozasiran 25 mg reduced fasting triglyceride levels by approximately 80% at 10 months in patients with familial chylomicronemia syndrome (FCS) and was associated with a lower incidence of pancreatitis compared with placebo. This provides supportive, yet not definitive, evidence for pancreatitis prevention as the PALISADE trial was powered to investigate triglyceride lowering. Across completed clinical studies, plozasiran demonstrated a generally favorable safety profile, with a low incidence of thrombocytopenia and adverse events primarily limited to abdominal pain, nasopharyngitis, headache, and nausea. Hyperglycemia was observed in some patients with preexisting diabetes or prediabetes at baseline. Ongoing phase 3 trials (SHASTA-3, SHASTA-4, SHASTA-5, SHASTA-10, MUIR-3 and CAPITAN) are further evaluating the efficacy and safety of plozasiran in broader populations with hypertriglyceridemia, including its potential role in reducing cardiovascular risk and preventing pancreatitis. Compared with earlier ApoC-III-targeted antisense oligonucleotides, plozasiran offers the advantages of less frequent dosing, sustained pharmacodynamic effects, and potentially a more favorable tolerability profile based on indirect evidence, positioning it as a promising therapeutic option for patients with FCS and other severe hypertriglyceridemia disorders inadequately managed with existing therapies.
2026-07-23 | Familial Chylomicronemia Syndrome Due to a Homozygous LPL c.644G>A Variant and Response to Volanesorsen in Colombia: A Case Report.
Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by persistent severe hypertriglyceridemia and recurrent acute pancreatitis, and is frequently misdiagnosed as multifactorial hypertriglyceridemia. We report the case of a 57-year-old Colombian male with recurrent acute pancreatitis and severe hypertriglyceridemia peaking at 4,350 mg/dL, refractory to fibrates, statins, and omega-3 fatty acids, with persistently low low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels. Secondary causes were excluded, and chronic valproic acid therapy was identified as a potential aggravating factor. A Moulin score of 10 points classified FCS as highly probable, and next-generation sequencing confirmed a homozygous pathogenic LPL variant, NM_000237.3.644G>A, p.(Gly215Glu), associated with loss of enzymatic activity. Following diagnostic confirmation, volanesorsen produced a sustained triglyceride reduction, with no new episodes of pancreatitis during uninterrupted therapy. This case underscores the importance of suspecting FCS in patients with refractory severe hypertriglyceridemia and recurrent pancreatitis. Molecular diagnosis enables access to precision medicine-based strategies with a meaningful impact on clinical outcomes and quality of life.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
2026-05-26 | Comparative efficacy and safety of olezarsen vs plozasiran for familial chylomicronemia syndrome: A matching-adjusted indirect comparison.
Familial chylomicronemia syndrome (FCS) is a rare genetic form of primary hypertriglyceridemia with an increased risk of acute pancreatitis (AP). Apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran, provide therapeutic approaches to reduce triglycerides in patients with FCS. To compare the efficacy and safety of olezarsen (Balance) with plozasiran (PALISADE) in FCS. An anchored matching-adjusted indirect comparison was conducted. Outcome analyses included only the approved dosages of study therapies, while the AP analysis also pooled high- and low-dose regimens. Analyses showed no statistically significant differences in 52-week efficacy or safety. Mean differences (olezarsen vs plozasiran) in triglycerides and apoC-III reduction were -15.5% (95% CI: -76.2, 45.2) and -8.4% (95% CI: -69.7, 53.0). Relative risks of AP, treatment-emergent, and serious adverse events were 0.70 (95% CI: 0.07, 6.66), 0.81 (95% CI: 0.58, 1.13), and 0.50 (95% CI: 0.10, 2.58). Overall, there was no evidence of differences in efficacy or safety between olezarsen and plozasiran in the treatment of patients with FCS.
2026-04-21 | Clinical identification of familial chylomicronemia syndrome and novel therapeutic options.
Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder driven by both genetic susceptibility and secondary factors. Most patients with severe HTG (triglyceride [TG] >10 mmol/L [>885 mg/dL]) have multifactorial chylomicronemia syndrome (MCS) while only a few have familial chylomicronemia syndrome (FCS), a rare autosomal recessive condition. We summarize the pathophysiology of severe HTG, emphasizing impaired intravascular lipolysis of TG-rich lipoproteins and the regulatory role of apolipoproteins (apo), particularly apo C-III. We outline features that distinguish FCS from MCS and discuss diagnostic strategies, including clinical scoring systems and targeted genetic testing. Current management approaches, including responses to conventional TG-lowering therapies and emerging biologic therapies targeting apo C-III, are examined. We searched PubMed for all English language literature focusing on the search terms 'chylomicronemia,' 'familial chylomicronemia syndrome,' 'multifactorial chylomicronemia syndrome,' 'hypertriglyceridemia,' 'APOC3 inhibition,' 'antisense oligonucleotides,' and 'apolipoprotein C-III.' Differentiating FCS from MCS is critical because RNA-based inhibition of apo C-III has transformed the therapeutic landscape for FCS patients. These agents provide substantial, durable TG lowering, and meaningful reductions in pancreatitis risk, although cardiovascular benefit remains uncertain. Future efforts should focus on optimizing diagnostic pathways, assessing cardiovascular outcomes, and determining long-term safety of these novel biologic therapies.
other
2026-06-17 | Heterozygosity for pathogenic variants in familial chylomicronemia syndrome genes: from carrier state to complex trait.
Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
2026-05-01 | Abstract Fri027: Apob18, An Inhibitor Of Endothelial Cell Lipoprotein Uptake, Reduces Vascular Inflammation
Hypertriglyceridemia is increasingly recognized as a key driver of endothelial activation and atherosclerosis. We recently reported that hypertriglyceridemia caused by induced global lipoprotein lipase-deficiency ( iLpl -/- ) trigger endothelial inflammatory signatures and accelerated aortic plaque development in LDL receptor knockout ( Ldlr -/- ) mice, underscoring the pathogenic role of nascent triglyceride (TG)-rich lipoproteins (TRLs) in vascular disease. We also showed that a protein fragment comprising the N-terminal 18% of apolipoprotein B100 (ApoB18) blocks endothelial cell uptake of chylomicrons. In this study, we investigated the effects of liver-targeted adeno-associated virus (AAV)-mediated expression of ApoB18 (TBG-AAV8-ApoB18) on vascular inflammation in Ldlr -/- and iLpl -/- /Ldlr -/- mice following 12 weeks of Western diet feeding. An empty TBG-AAV8 was used as control. Compared with Ldlr -/- mice, iLpl -/- /Ldlr -/- mice exhibited markedly elevated circulating TG levels (1193 mg/dL vs. 264 mg/dL; n=14). Single-cell RNA-sequencing of the aorta (n=4) revealed robust upregulation of inflammatory genes, including Thbs1, Vcam1, Icam1, Tgfb1, Nfkb1, Klf2, and Klf4 in endothelial cells, macrophages, and smooth muscle cells, indicating widespread vascular inflammation in iLpl -/- /Ldlr -/- mice compared with Ldlr -/- mice. Pathway enrichment analysis further demonstrated that global LPL-deficiency elevated multiple pro-atherogenic and inflammatory signaling networks, including lipid and atherosclerosis pathways as well as MAPK signaling, consistent with an enhanced cellular response to dysregulated lipid metabolism. TBG-AAV8-ApoB18 treatment attenuated the expression of these inflammatory genes in both genotypes. Assessment of circulating ApoB18 showed that this protein was expressed at a molar ratio of less than 10% of both lipoprotein ApoB100 and ApoB48 and in vitro competition studies confirmed that this fragment appeared to be a better ligand for both scavenger receptor BI and activin-like kinase 1 than lipoprotein-associated ApoB , since competition with ApoB18 at a molar ratio as low as 1% significantly inhibited EC uptake of both LDL (48.2% uptake compared to control, p<0.0001) and chylomicrons (42.3% uptake compared to control, p<0.0001). These findings demonstrate that AAV-mediated ApoB18 expression attenuates vascular inflammation, with likely implications for atherosclerosis enhanced by endothelial cell uptake of ApoB-containing lipoproteins.
2025-11-15 | An Updated Review of Novel Triglyceride-Lowering Therapies in Adults with Familial Chylomicronemia Syndrome.
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder resulting in hypertriglyceridemia. Historically, treatment options for this patient population have been limited as available triglyceride-lowering medications are often ineffective. Recently, new pharmacological agents targeting apolipoprotein C-III (apoC-III) production have been found to effectively and substantially lower triglyceride levels. A literature search in PubMed and EMBASE was conducted from January 2013 to July 2025 using keywords "familial chylomicronemia syndrome", "olezarsen", "volanesorsen", and "plozasiran". Phase III trials evaluating safety and efficacy of volanesorsen, olezarsen, and plozasiran were included. From 1376 articles, 4 phase III trials fulfilled the inclusion criteria. Triglyceride (TG) levels were reduced by 73-77% with volanesorsen, a least-square means reduction in TGs between 22.4 and 43.5 percentage points with olezarsen, and a 78-80% reduction in TGs with plozasiran when compared with placebo. The number of acute pancreatitis events was also lower with the study medications versus placebo. These new apoC-III lowering medications provide a novel treatment approach for patients with FCS, a population long without effective pharmacological treatment options. Provider familiarity with the availability and purpose of these medications will allow patients to receive the best therapy available to manage FCS.
2025-03-27 | Optimization of adeno-associated viral (AAV) gene therapies vectors for balancing efficacy, longevity and safety for clinical application.
Adeno-associated viral (AAV) vectors are an ideal platform for gene therapy due to their ability to deliver therapeutic cargos safely and effectively across various target organs. Their low immunogenicity contributes to long-lasting therapeutic effects. However, recent insights highlight the significance of CpG content within AAV vectors, where unmethylated CpG dinucleotides can trigger a TLR9-mediated immune response, leading to the rapid elimination of transduced cells. Clinical evidence indicates an inverse relationship between CpG content and therapeutic success, with lower CpG counts correlating with sustained transgene expression. Here, we sought to optimize a novel, CpG-rich AAV8 vector, referred to as pVR59, designed for treating lipoprotein lipase deficiency (LPLD). We strategically reduced CpG levels in pVR59, resulting in the development of pNC182, a CpG-depleted vector that maintains therapeutic efficacy. A single intramuscular injection of pNC182 demonstrated comparable effectiveness to pVR59 in normalizing lipemia and hypertriglyceridemia in LPLD mouse models, with a 38% reduction in total CpG count. These findings support the clinical application of pNC182 as a safe, long-lasting AAV gene therapy for LPLD and provide a framework for future AAV vector designs aimed at maximizing therapeutic efficacy while minimizing immunogenic responses in human settings.
2025-03-06 | Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia.
Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability. To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab. A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients. After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L). The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Familial lipoprotein lipase deficiency.
2 orphan drug designations for Familial lipoprotein lipase deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adeno-associated vector expressing the human lipoprotein lipase protein | gene therapies | FDA | uniQure B.V. | |
Alipogene tiparvovec [Glybera] | gene therapies | EMA | uniQure Biopharma B.V |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.