Transition of patients with familial chylomicronaemia syndrome from volanesorsen to olezarsen: safety and pharmacokinetic results
Bibliographic record
Abstract
Abstract Background Familial chylomicronaemia syndrome (FCS) is a rare genetic disorder of lipoprotein lipase deficiency resulting in severe hypertriglyceridaemia and pancreatitis risk. Volanesorsen is a weekly-injected antisense oligonucleotide (ASO) designed to degrade APOC3 mRNA that is approved as an adjunct to diet to treat FCS in the EU, UK, and Brazil. Olezarsen is an investigational monthly-injected ASO-GalNAC3 conjugate also designed to degrade APOC3 mRNA, but directed to hepatocytes, resulting in more potency and less systemic exposure and making it a potential alternative to volanesorsen for FCS. Purpose This interim analysis of an open-label phase 3 trial evaluated olezarsen safety and pharmacokinetics in patients (pts) with FCS previously treated with volanesorsen. Methods Adults with FCS with prior volanesorsen treatment, or actively participating in an expanded access programme (US and Canada), started olezarsen 80 mg by subcutaneous injection every 4 weeks after a minimum washout of 6 weeks. Historical volanesorsen laboratory and safety data were unavailable. The primary objective was to assess safety from changes vs baseline in platelet count, liver enzymes, and renal function; bleeding events; and adverse events. Pharmacokinetic measurements included plasma volanesorsen and olezarsen concentrations. Immunogenicity was assessed by measuring anti-drug antibodies (Abs). Results Of 24 pts enrolled, the majority were female (n=13; 54.2%) and White (n=21; 87.5%), with mean age of 49.1 years; 20 (83.3%) had genetically and 4 (16.7%) clinically validated FCS, all had history of acute pancreatitis (or symptoms suggestive of pancreatitis requiring hospitalisation or emergency room/urgent care visit; mean, 3.4 episodes within 5 years) and 5 (20.8%) of thrombocytopaenia. Time since last volanesorsen dose was 42—1118 days. Baseline fasting triglyceride (median [interquartile range (IQR)], 18.6 [9.6,34.0] mmol/L [1648 (852,3007) mg/dL]; mean [standard deviation (SD)], 25.5 [20.5] mmol/L [2256 (1812) mg/dL]) and apolipoprotein C-III (median [IQR], 0.2 [0.1,0.4] g/L [16.1 (12.4,39.0) mg/dL]; mean [SD], 0.3 [0.2] g/L [25.9 (19.5) mg/dL]) levels were elevated. During a mean (SD) of 329 (95) days of olezarsen 80 mg treatment, no pts experienced hepatic failure, renal impairment, major bleeding events, or platelet count below the prespecified threshold of 50,000 mm³ (Table 1). Olezarsen levels at trough were elevated during the first 3 months, mainly due to residual volanesorsen levels in pts with washout <90 days (Figure 1). Eleven (45.8%) pts had treatment-emergent anti-olezarsen Abs, of whom 5 (20.8%) had anti-volanesorsen Abs, with no impact on safety or efficacy; pts with vs without anti-drug Abs had higher olezarsen trough levels (mean, 4.4–7.8 ng/mL vs 1.1 ng/mL). Conclusions In this interim analysis, olezarsen was safe and well tolerated in pts with FCS previously treated with volanesorsen after a minimum washout of 6 weeks.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".