What are the considerations for using Lepodisiran (a medication for hypertriglyceridemia and liver disease) in an adult patient with a history of elevated triglyceride levels or liver disease?

Lepodisiran for Elevated Lipoprotein(a)

What is Lepodisiran?

Lepodisiran is an investigational GalNAc-conjugated small interfering RNA (siRNA) therapy that targets hepatic synthesis of apolipoprotein(a), achieving profound and sustained reductions in lipoprotein(a) [Lp(a)] levels of up to 97% with extended dosing intervals. 1, 2

Lepodisiran works by inhibiting LPA gene transcription in the liver, thereby reducing production of apo(a), which is essential for assembly of Lp(a) particles 3. Unlike traditional lipid-lowering therapies (statins, fibrates, omega-3 fatty acids), which have minimal to no effect on Lp(a) levels, lepodisiran specifically targets this independent cardiovascular risk factor 3.

Clinical Efficacy and Dosing

Phase 1 Trial Results

In a dose-ascending trial of 48 adults with elevated Lp(a) ≥75 nmol/L, single subcutaneous doses of lepodisiran produced dose-dependent reductions 1:

• 4 mg dose: -41% median reduction in Lp(a) 1
• 12 mg dose: -59% median reduction 1
• 32 mg dose: -76% median reduction 1
• 96 mg dose: -90% median reduction 1
• 304 mg dose: -96% median reduction 1
• 608 mg dose: -97% median reduction, with -94% reduction sustained at day 337 (48 weeks) 1

Phase 2 Trial Results (ALPACA)

In 320 participants with median baseline Lp(a) of 253.9 nmol/L, lepodisiran administered at baseline and day 180 demonstrated 2:

• 16 mg dose: -40.8 percentage point placebo-adjusted reduction from day 60-180 2
• 96 mg dose: -75.2 percentage point reduction 2
• 400 mg dose (pooled groups): -93.9 percentage point reduction from day 60-180, and -88.5 to -94.8 percentage point reduction from day 30-360 depending on whether second dose was given 2

The extended duration of action allows for dosing intervals of 6-12 months, with plasma concentrations peaking within 10.5 hours and becoming undetectable by 48 hours after administration. 1

Safety Profile

Lepodisiran demonstrated a favorable safety profile across clinical trials 1, 2:

• Serious adverse events: Only 1 serious adverse event occurred in the Phase 1 trial (48 participants), and 35 serious adverse events in Phase 2 (320 participants), with none deemed related to lepodisiran by investigators 1, 2
• Injection-site reactions: Dose-dependent, generally mild reactions occurred in up to 12% of participants receiving the highest dose 2
• No treatment discontinuations or deaths related to lepodisiran 2

Clinical Context: Lp(a) as a Cardiovascular Risk Factor

Elevated Lp(a) is an independent, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis 1, 3. Traditional risk reduction strategies including diet, exercise, statins, fibrates, and omega-3 fatty acids have minimal impact on Lp(a) levels 3.

Lepodisiran represents a fundamentally different therapeutic approach compared to triglyceride-lowering therapies. While the evidence provided includes extensive guidelines on hypertriglyceridemia management 4, 5, 6, 7, these are not directly applicable to Lp(a) reduction, as Lp(a) and triglycerides are distinct lipid parameters with different pathophysiology and treatment approaches.

Current Status and Future Directions

Lepodisiran is currently investigational and not FDA-approved 1, 2, 3. Ongoing Phase 3 trials are evaluating long-term safety, clinical efficacy, and impact on ASCVD outcomes. 3

The drug's mechanism differs from other siRNA therapies mentioned in the evidence, such as plozasiran (which targets APOC3 for severe hypertriglyceridemia) 8 and inclisiran (which targets PCSK9 for LDL-C reduction) 4.

Key Considerations for Future Use

• Target population: Adults with elevated Lp(a) levels (≥75 nmol/L or ≥30 mg/dL) at increased cardiovascular risk 1
• Administration: Subcutaneous injection with extended dosing intervals (potentially every 6-12 months based on Phase 2 data) 2
• Monitoring: Lp(a) levels should be measured to assess response 1, 2
• Cardiovascular outcomes data: Currently pending from ongoing Phase 3 trials 3

The profound and sustained Lp(a) reduction achieved with lepodisiran, combined with its favorable safety profile and convenient dosing schedule, positions it as a potentially transformative therapy for patients with elevated Lp(a)-mediated cardiovascular risk, pending confirmation of clinical benefit in outcome trials. 3