The medical community is abuzz with the potential of Lepodisiran, an investigational siRNA therapy developed by Eli Lilly, to significantly reduce lipoprotein(a) (Lp[a]) levels. Lp(a) is a genetically determined molecule in the blood that carries cholesterol and is a known independent risk factor for cardiovascular disease (CVD). Unlike other risk factors, such as blood cholesterol levels, which can be influenced by lifestyle, Lp(a) levels are primarily inherited and remain relatively stable throughout life. High levels of Lp(a) increase the risk of cardiovascular events such as heart attacks, stroke, and aortic stenosis.
Early results from the Phase II ALPACA trial (NCT05565742) and other studies have demonstrated Lepodisiran's ability to reduce Lp(a) levels by up to 94%. While this is a scientifically impressive achievement, the clinical community remains cautiously optimistic. This article will delve into the potential of Lepodisiran, the concerns surrounding its adoption, and the evidence needed to solidify its place in cardiovascular risk management.
The Promise of Lepodisiran
Significant Lp(a) Reduction
Lepodisiran has shown remarkable efficacy in reducing Lp(a) levels. In the Phase 2 clinical trial, a single dose of the experimental therapy safely reduced average blood levels of lipoprotein(a) by 94% during the following 180 days. During a full year (360 days) after one dose, lipoprotein(a) levels were reduced by 88.5%. These findings, presented at the American College of Cardiology's annual meeting in Chicago and published in the New England Journal of Medicine, highlight the potential of Lepodisiran to address a major unmet need in cardiovascular risk management.
The ALPACA trial, a randomized, placebo-controlled study, enrolled 320 participants aged 40 years and above. The results achieved the trial’s primary endpoint with a placebo-adjusted time-averaged percent change from baseline in serum lipoprotein(a) concentration from day 60 to day 180 of -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran cohort, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg cohort, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg cohorts. Corresponding changes from day 30 to day 360 were -41.2 percentage points in the 16-mg cohort (95% CI, -55.4 to -22.4), -77.2 percentage points in the 96-mg cohort (95% CI, -81.8 to -71.5), -88.5 percentage points 400-mg plus placebo cohort (95% CI, -90.8 to -85.6), and -94.8 percentage points in the 400-mg-400-mg cohort (95% CI, -95.9 to -93.4).
Addressing an Unmet Need
Approximately 25% of the global population has elevated levels of lipoprotein(a), putting them at a significantly higher risk of cardiovascular events such as heart attacks and strokes. Unfortunately, there are no approved cholesterol-lowering therapies specifically for this genetic risk factor, and lifestyle changes like diet and exercise do not provide meaningful reductions. Traditional approaches to reduction in the risk of cardiovascular disease, including lifestyle alterations and statin therapy, have minimal effects on serum lipoprotein(a) concentrations. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors slightly reduce lipoprotein(a) concentrations but have not been studied in dedicated prospective, randomized trials assessing cardiovascular outcomes among persons with elevated lipoprotein(a) concentrations. No pharmacologic therapies have been approved by regulatory authorities, although plasma apheresis is approved in some countries.
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Lepodisiran, by targeting the hepatic production of apolipoprotein(a), offers a potential solution to this unmet need.
Long-Term Durability
One of the appealing aspects of Lepodisiran is its long-lasting effect. The Phase 2 trial demonstrated that Lp(a) levels remained significantly below baseline for an extended period after a single dose. Lp(a) reduction from days 30 to 360 was 88.5% after a single dose and 94.8% after 2 doses 180 days apart. Lp(a) levels remained 53.4% below baseline 540 days after a single dose and 74.2% 360 days after a second dose. This durability could translate to less frequent dosing and improved patient adherence.
Concerns and Hesitations
Despite the promising results, several concerns could hinder the widespread adoption of Lepodisiran.
Novel RNA-Based Mechanism
Lepodisiran's novel RNA-based mechanism raises concerns among some physicians. As a GP noted, “As with any novel RNA-based therapy, cautious optimism is warranted." The long-acting nature of the therapy, while convenient, raises red flags if adverse effects appear. “Lepodisiran may suppress Lp(a) for months with a single dose - which is convenient, but also risky if side effects emerge." A GP asked: “What unexpected immune or off-target effects might surface with chronic RNA therapy?
Safety and Side Effects
A primary concern revolves around the potential side effects and risks associated with Lepodisiran. As one Orthopedic Surgeon noted, “I would like to know side effects and risks." While the Phase 2 trial reported no major safety concerns, up to 10% of patients had mild, injection site reactions for a short time, such as pain or redness. However, longer-term studies with larger patient populations are needed to fully assess the safety profile of Lepodisiran.
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Lack of Cardiovascular Outcome Data
While Lepodisiran effectively reduces Lp(a) levels, the ultimate goal is to demonstrate a reduction in major cardiovascular events, such as heart attacks and strokes. Currently, there is limited evidence to support this. As one family medicine doctor commented: “Sounds great, but no evidence of reduction in major cardiovascular events." A Cardiologist cautioned: “Decreasing Lp(a) may not be so good-we need to be shown it’s clinically useful, preferably hard points such as mortality."
Cost and Accessibility
The cost of Lepodisiran and its accessibility to patients are also significant concerns. One in four physicians on Sermo worry about affordability and real-world access. “The cost to patient is one concern," said an Internal Medicine specialist. Even if approved, administrative hurdles and insurance coverage may pose challenges. An Anaesthesiologist remarked: “Clinical data should support the introduction of any intervention. Then the cost/benefit analysis. Then the fight to get it paid for by insurers (in the US)," reminding us that even approved drugs face obstacles before reaching patient hands.
Integration with Existing Therapies
Questions remain about how Lepodisiran will integrate alongside existing therapies like statins and PCSK9 inhibitors. A GP asked: “How will Lepodisiran integrate alongside statins and PCSK9 inhibitors?" Further research is needed to determine the optimal combination of therapies for patients with elevated Lp(a).
The Path Forward
To gain widespread acceptance, Lepodisiran needs to overcome the existing concerns and provide compelling evidence of its clinical benefits.
Phase 3 Cardiovascular Outcome Trial
The ongoing Phase 3 cardiovascular outcome trial is crucial for determining the effectiveness of Lepodisiran in reducing cardiovascular events. This study, sponsored by Eli Lilly and Company in collaboration with Dr. Nissen and Cleveland Clinic, aims to learn more about the safety and effectiveness of the drug Lepodisiran (LY3819469) in lowering Lp(a) levels and reducing cardiovascular events in people with cardiovascular disease or who are at risk for a first cardiovascular (CV) event and provide additional evidence for the potential clinical benefits of Lepodisiran. The results of this trial will be critical in determining the future of Lepodisiran.
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Addressing Safety Concerns
Continued monitoring and reporting of adverse events in clinical trials and post-market surveillance are essential to establish the long-term safety profile of Lepodisiran. Transparency and open communication about potential risks will be crucial in building trust among physicians and patients.
Demonstrating Cost-Effectiveness
To ensure accessibility, it will be important to demonstrate the cost-effectiveness of Lepodisiran. This may involve conducting economic analyses to compare the cost of Lepodisiran to the potential savings from reduced cardiovascular events. Negotiations with insurance companies and government agencies will also be necessary to secure coverage for the therapy.