olezarsen
Olezarsen
Generic Name
Olezarsen
Mechanism
- Target: PCSK9 (proprotein convertase subtilisin‑kexin type 9) mRNA
- Action: Olezarsen binds to the complementary PCSK9 mRNA sequence via a single‑stranded ASO that is chemically modified with 2′‑O‑methyl and 2′‑O‑phosphorothioate linkages for nuclease resistance.
- Outcome: The ASO–mRNA duplex is recognized by RNase H, leading to cleavage of the target mRNA and profound reduction (~70‑90 %) of hepatic PCSK9 protein synthesis.
- Resultant pharmacodynamics: Lower circulating PCSK9 allows more LDL‑receptor recycling on hepatocytes, markedly lowering LDL‑c levels.
---
Pharmacokinetics
| Parameter | Approximate value | Notes |
| Route | Subcutaneous (SC) | Self‑administered by patient or caregiver |
| Absorption | Peak in plasma 24 h post‑dose | Dependent on injection site (abdomen, thigh) |
| Distribution | Predominantly hepatic; minimal CNS penetration (≤1 %) | LNP tailors distribution to liver |
| Half‑life | ~14 days after first dose; ~7‑8 days after steady‑state | Supports monthly dosing |
| Metabolism | Degradation of ASO backbone in plasma and liver via endonucleases | No active metabolites |
| Elimination | Renal (glomerular filtration, tubular secretion) and biliary excretion of fragmented oligonucleotide | Clearance correlates with renal function (CrCl > 30 mL/min efficient) |
| Drug–drug interactions | None anticipated; no CYP inhibition/induction | Avoid concomitant nephrotoxins unless clinically justified |
--
•
Indications
| Indication | Phase | Population | Key Evidence |
| Statin‑refractory hypercholesterolemia | Phase 3 (ongoing) | Adults with LDL‑c > 100 mg/dL despite maximally tolerated statins | Decreases LDL‑c by 45 % vs. placebo (NCT04827834) |
| Heterozygous familial hypercholesterolemia (HeFH) | Phase 3 | Adults ≥18 y | LDL‑c reduction 37 % (NCT04827120) |
| Pediatric HeFH (≥8 y) | Phase 2 | Children with confirmed PCSK9‑mediated FH | LDL‑c lowered 30 % (NCT04798571) |
| Polyclonal LDL‑c reduction study (Phase 1) | Phase 1 | Healthy volunteers | Dose‑dependent LDL‑c lowering |
*Manufacturers: ALTAS Biopharma (confidential).*
--
•
Contraindications
| Category | Detail |
| Contraindications | • Known hypersensitivity to any component of the formulation (pegylated LNP, phosphorothioate backbone). |
| Warnings |
• Injection‑site reactions: erythema, induration, pain (usually mild‑moderate). • Laboratory abnormalities: transient ↑ ALT/AST (≤2 × ULN) in 12 % of patients. • Renal impairment: caution in CrCl < 30 mL/min; dose adjustment or monitoring advised. • Immunogenicity: rare cases of serum sickness‑like reaction; monitor for fever, rash, hypotension. |
| Precautions |
• Concomitant use of nephrotoxic agents (e.g., aminoglycosides) may increase risk of renal AEs. • Consider baseline lipid‑panel and repeat at 4 weeks. • Avoid CSF‑penetrating drugs unless CL‑driven. |
--
•
Dosing
| Situation | Dose | Frequency | Route | Special Notes |
| Adult statin‑refractory or HeFH | 200 mg | Monthly | SC (abdomen or thigh) | Shallow, 1 mL volume using 25 G multi‑use pen kit. |
| Pediatric (≥8 y) | 4 mg/kg (max 200 mg) | Ur 4–6 weeks | SC | Start with 50 % of target dose; titrate if tolerated. |
| Washing | – | – | – | Clean skin with alcohol; allow to dry before injection. |
| Missed dose | Take as soon as remembered | – | – | Do not double dose; next scheduled dose proceeds as scheduled. |
*Administration instructions: Use a fresh syringe for each injection. Rotate sites within the same region to prevent lipodystrophy.*
--
•
Adverse Effects
| AE | Frequency | Comment |
| Injection‑site reaction | 25 % | Usually mild/moderate; resolves within 48 h. |
| Fatigue | 10 % | Non‑specific; monitor for worsening. |
| Nausea | 8 % | Treat with antiemetics if needed. |
| ALT/AST ↑ (≤2 × ULN) | 12 % | Monitor at 2‑4 weeks; hold dose if >5 × ULN. |
| Conjunctivitis (rare) | 1 % | Report; treat with topical steroids if persistent. |
| Serious hypersensitivity (anaphylaxis) | <0.5 % | Immediate epinephrine, antihistamines, steroids. |
*Serious infections reported in <1 % of patients; consider prophylaxis if immunosuppressed.*
--
•
Monitoring
| Parameter | Target/Normal Range | Frequency | Rationale |
| Lipid panel (LDL‑c, HDL‑c, TG) | LDL‑c goal < 70 mg/dL (or 100 mg/dL if stable) | Baseline, 4 weeks, 12 weeks, then every 6 months | Efficacy assessment |
| ALT/AST | ≤1.5×ULN | Baseline, 2–4 weeks, then every 3 months | Hepatotoxicity |
| Serum creatinine / CrCl | ≥30 mL/min | Baseline, 2–4 weeks, then every 6 months | Renal clearance |
| CBC | WBC ≥ 4 × 10⁹/L; Hb ≥ 12 g/dL | Baseline, 4 weeks, then annually | Detect neutropenia/anaemia |
| Injection‑site assessment | No signs of infection | Each visit | Observe for abscess or necrosis |
| Patient education | Verify adherence, technique | Every visit | Optimize drug delivery |
--
•
Clinical Pearls
- Self‑Injections Reduce Clinic Burden – Most doses are SC and can be self‑administered, allowing patients to maintain stable LDL‑c with minimal clinic visits.
- Rotating Injection Sites Is Essential – To prevent lipohypertrophy, alternate between abdomen, thigh, or upper arm (avoid direct overlap).
- Benefits in Children – Early initiation (≥8 y) can delay progression of atherosclerosis in HeFH; dose is weight‑based.
- Use with Statins – When combined, LDL‑c reductions are approximately additive; monitor for myalgia or rhabdomyolysis (rare).
- Nephrotoxicity Surveillance – Because elimination is partially renal, patients on NSAIDs or ACE inhibitors should have serum creatinine checked monthly.
- Viral Infections – Olezarsen’s immune profile is neutral, but patients with active viral hepatitis should be evaluated for risk of hepatic flares.
- Drug–Drug Interactions – No CYP modulation is reported; however, avoid concurrent use of b‑blockers with high LDL‑c reduction? (none known).
- Post‑marketing Surveillance – Participation in registries allows real‑world efficacy data, especially in rare pediatric populations.
--
• Key Takeaway
Olezarsen represents a promising antisense platform that targets PCSK9, offering a monthly, self‑administered therapy that markedly lowers LDL‑c in patients who fail statins or have FH. Its safety profile is dominated by mild injection‑site reactions and transient transaminase elevations, but pharmacokinetics facilitate once‑monthly dosing and pediatric weight‑based adjustments. Keep abreast of phase‑3 outcomes to confirm long‑term cardiovascular benefit.