What clinical trials have been conducted for Inclisiran sodium?

Introduction to Inclisiran Sodium

Inclisiran sodium is a first-in-class small interfering RNA (siRNA) designed to lower low-density lipoprotein cholesterol (LDL-C) levels through a unique mechanism targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA. It has emerged as an innovative therapeutic option for patients with hypercholesterolemia, particularly for those who cannot achieve LDL-C goals with conventional therapies such as statins, or for patients who demonstrate statin intolerance.

Mechanism of Action

Inclisiran employs RNA interference to specifically bind to and cleave PCSK9 mRNA in hepatocytes. By inhibiting the translation of PCSK9, the drug indirectly increases the availability of LDL receptors on the liver surface, thereby enhancing the clearance of LDL-C from the bloodstream. Its design includes conjugation with N-acetylgalactosamine (GalNAc), which ensures liver-specific uptake and mitigates off-target effects. Notably, even though inclisiran has a short plasma half-life (around 5–10 hours), its effect on lowering PCSK9 and LDL-C is prolonged, lasting months after administration due to the durable gene-silencing effect.

Therapeutic Indications

Inclisiran is primarily indicated for the treatment of hypercholesterolemia—both primary hypercholesterolemia (familial and non-familial) and mixed dyslipidemia—in adult patients who are either not adequately controlled on maximally tolerated doses of statins or are statin-intolerant. Additional potential indications include use in patients with atherosclerotic cardiovascular disease (ASCVD) or risk equivalents. Furthermore, clinical investigations have extended to special populations such as children with heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia and adolescents with familial hypercholesterolemia. Post-marketing surveillance trials and real-world studies have also been initiated in various regions including India and Korea to further establish the benefits and safety of inclisiran in clinical practice.

Overview of Clinical Trials

Clinical development programs for inclisiran have followed a well-structured pathway across early phase studies to large phase III trials, with key endpoints including changes in LDL-C, PCSK9 levels, safety and tolerability assessments, and – in some analyses – cardiovascular outcomes in high-risk patients.

Phases of Clinical Trials

The clinical trial series for inclisiran can broadly be categorized as follows:

- Phase I/II Trials: Early dose-escalation and proof-of-concept trials (e.g., ORION-1) established the optimal dosing regimen and provided initial evidence of LDL-C and PCSK9 reductions, along with safety and tolerability profiles.
- Phase III Trials: Larger, randomized, double-blind, placebo-controlled studies (e.g., ORION-9, ORION-10, ORION-11) further confirmed the robust efficacy of inclisiran in lowering LDL-C by approximately 50% with a twice-yearly dosing schedule. These trials also began to assess secondary outcomes such as incidence of cardiovascular events and the effect in various high-risk populations.
- Phase IV/Real-World Studies: Post-approval real-world studies have been initiated to monitor the safety and effectiveness of inclisiran in broader populations and diverse geographic regions (e.g., Indian patients and post-marketing surveillance in Korea).

Regulatory Framework for Clinical Trials

Inclisiran clinical trials have been conducted under internationally recognized regulatory guidelines. Early trials were submitted to regulatory bodies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for review. With consistent demonstration of efficacy and safety profiles, inclisiran received regulatory approval in Europe for specific hypercholesterolemia indications. Many of these trials were registered in public clinical trial databases (e.g., ClinicalTrials.gov with identifiers NCT03399370, NCT03400800, etc.). In parallel, post-marketing and real-world studies are monitored under regulatory frameworks that require ongoing safety and efficacy data to ensure that the outcomes observed in controlled trial environments are reproducible in routine clinical practice.

Analysis of Conducted Clinical Trials for Inclisiran Sodium

The body of clinical evidence on inclisiran is both expansive and multifaceted. Studies have ranged from early dose finding and pharmacokinetic/pharmacodynamic (PK/PD) studies to large-scale phase III efficacy and safety trials in diverse patient populations. Below, we detail the key trials, outcomes, and safety findings.

Key Trials and Their Designs

Several landmark trials and studies have been conducted:

- ORION-1 Trial:
This pivotal multi-center, double-blind, placebo-controlled, phase II trial was the first to evaluate inclisiran in patients at high risk for cardiovascular events. Patients received single or multiple doses (with regimens including one versus two doses) to assess dose-dependent lowering of PCSK9 and LDL-C. The study demonstrated reductions in LDL-C ranging from 27.9% to 41.9% with one dose and improvements up to approximately 52.6% with two doses, with durable effects beyond 6 months.

- ORION-9 Trial:
Specifically designed for patients with heterozygous familial hypercholesterolemia (HeFH), ORION-9 enrolled patients with baseline LDL-C levels despite maximum tolerated statin therapy. In this phase III trial, patients were randomized to receive inclisiran (administered subcutaneously on Day 1, Day 90, and every 6 months thereafter) or placebo. The trial demonstrated significant LDL-C reductions (approximately 39.7%–50% reductions compared to placebo) and established the effective dosing schedule of twice-yearly maintenance injections.

- ORION-10 and ORION-11 Trials:
Conducted in patients with atherosclerotic cardiovascular disease (ASCVD) or risk equivalents, these two phase III trials confirmed that inclisiran reduced LDL-C levels by approximately 52.3% in ORION-10 and by 49.9% in ORION-11 relative to placebo over an 18-month period. Both trials utilized a dosing regimen of an initial injection, a second dose at 3 months, then maintenance doses every 6 months. These trials also contributed to the evidence supporting the safety profile of inclisiran and provided promising exploratory data regarding the potential reduction in major adverse cardiovascular events (MACE).

- Trials in Special Populations:
Given the importance of treating dyslipidemia in younger patients and children, dedicated clinical trials have been initiated or are ongoing:
- A study to evaluate the efficacy and safety of inclisiran in children (6 to less than 12 years) with heterozygous familial hypercholesterolemia was conducted.
- Another trial focused on children with homozygous familial hypercholesterolemia (aged 2 to less than 12 years).
- An additional trial evaluating the treatment of adolescents (12 to less than 18 years) with heterozygous familial hypercholesterolemia (the ORION-16 trial) has been reported.
These trials are aimed at determining whether the safety and efficacy profile observed in adults holds in younger populations, and they represent a forward-looking approach to addressing the life-long burden of hypercholesterolemia in familial cases.

- Real-World and Post-Marketing Studies:
Several studies are currently underway to evaluate the performance of inclisiran outside the controlled environment of clinical trials:
- A phase IV clinical study in Indian patients with primary hypercholesterolemia or mixed dyslipidemia has been registered and is designed to assess the safety and efficacy in a real-world patient population.
- A regulatory post-marketing surveillance study in Korea (rPMS) has been initiated to monitor the response of patients treated with inclisiran via pre-filled syringes.
- In Latin America, a study (LATAM LOWERS LDL-C) is assessing the outcomes after acute events in patients with atherosclerotic cardiovascular disease, adding an additional geographic perspective on the drug’s performance.

- Comparative and Exploratory Studies:
Some studies have been designed to compare inclisiran with other lipid-lowering treatments:
- A trial comparing the LDL-C lowering effects of inclisiran with bempedoic acid in patients with established ASCVD highlights the potential of inclisiran as an alternative or complementary approach.
- Other exploratory studies have looked at additional endpoints such as the effect of inclisiran on carotid plaque assessed by ultrasound and the use of inclisiran in acute coronary syndromes for early passivation of vulnerable plaques.
- Combination studies, such as the trial investigating pelacarsen (TQJ230) on background inclisiran therapy, have been conducted to evaluate whether further combination lipid-lowering strategies can maximize cardiovascular risk reduction.

Collectively, these trials represent a robust clinical program that has evaluated inclisiran across multiple phases, patient populations, and even compared its activity with other active lipid-lowering agents.

Outcomes and Efficacy

The results of the outstanding clinical trials have consistently demonstrated that inclisiran yields robust and durable reductions in LDL-C and circulating PCSK9 levels. Key findings include:

- LDL-C Reduction:
Across the ORION series of trials (ORION-9, ORION-10, ORION-11), inclisiran has produced reductions in LDL-C of approximately 50% when compared to placebo. For example, ORION-10 demonstrated a mean placebo-adjusted reduction of 52.3% at the 18-month follow-up, while ORION-11 achieved reductions of 49.9%. These magnitudes of LDL-C lowering are consistent regardless of the underlying patient population (ASCVD, HeFH, risk equivalents) and have been shown in multiple ethnic and regional populations.

- PCSK9 Reduction:
In addition to the lipid-lowering effects, inclisiran has been shown to reduce circulating PCSK9 levels by up to approximately 80%. This is integral for maintaining the increased receptor availability on hepatocytes and sustaining LDL-C reduction over time.

- Durability of Effect:
The dosing regimen of an initial injection, followed by a booster at 3 months, and then maintenance dosing every 6 months, is supported by data demonstrating a sustained effect. In the ORION-3 extension study, inclisiran was shown to maintain a time-averaged LDL-C reduction of over 50% for up to 22 months and even over 4 years in some patients. The durable nature of the response stands in contrast to some other lipid-lowering agents that require more frequent dosing.

- Cardiovascular Outcome Trends:
Although the trials were primarily designed to assess LDL-C lowering, exploratory analyses have suggested trends toward reduction in major adverse cardiovascular events (MACE). In a pooled patient-level analysis, a lower incidence of cardiovascular events was observed in inclisiran-treated patients (for example, 7.1% versus 9.4% in placebo-treated patients in one analysis), although these endpoints are considered exploratory and require further confirmation in outcome trials such as ORION-4.

These efficacy findings are noteworthy because, despite the relatively infrequent (twice-yearly) dosing, the consistency and magnitude of LDL-C reduction are on par with the most potent of available lipid-lowering strategies. Moreover, the effect on LDL-C lowering appears to be highly reproducible even across different subgroups and in real-world settings.

Safety and Adverse Effects

The safety profile of inclisiran has been carefully studied in all phases of its clinical development:

- General Tolerability:
In both phase II and phase III trials, inclisiran was generally well tolerated. The rates of serious adverse events were similar between the inclisiran and placebo groups. For instance, in ORION-10 and ORION-11 the incidence of adverse events was comparable between the treatment arms, although a slightly higher frequency of injection-site reactions was noted in the inclisiran-treated groups.

- Injection-Site Reactions:
The most common adverse event reported has been local injection-site reactions. These events, although more frequent in the inclisiran groups (with reported rates, for example, of 2.6% vs. 0.9% in ORION-10 and 4.7% vs. 0.5% in ORION-11), were predominantly mild, transient, and did not lead to discontinuation of the therapy.

- Hepatic and Renal Safety:
Across multiple studies, inclisiran has not demonstrated any evidence of clinically significant hepatotoxicity or nephrotoxicity. Furthermore, even in patients with renal impairment, the safety profile is preserved and no dose adjustments are necessary.

- Immunogenicity:
The incidence of treatment-induced antidrug antibodies has been low (reported in fewer than 5% of patients), and these did not appear to correlate with any changes in efficacy or safety outcomes.

- Long-Term Safety:
Data from extension studies (such as ORION-3 and early findings from ORION-8) suggest that the safety profile remains stable over long-term treatment, with no emergence of new adverse signals over a follow-up period extending up to 4–6 years in some analyses.

Overall, the benefit–risk profile of inclisiran in controlling LDL-C is solid, with a side effect profile that is considered manageable within the context of lipid-lowering therapy.

Implications and Future Directions

The robust clinical trial program for inclisiran sodium has far-reaching implications for therapy and ongoing research in dyslipidemia management and cardiovascular risk reduction.

Impact on Treatment Guidelines

The results from the extensive ORION trials and subsequent real-world studies have contributed to a paradigm shift in lipid-lowering therapy:

- Guideline Evolution:
The sustained and consistent LDL-C lowering effect achieved with twice-yearly dosing has the potential to influence clinical guidelines by providing an alternative to the conventional daily dosing required by statins or monoclonal antibody inhibitors of PCSK9. This improved adherence profile might lead to increased overall treatment effectiveness in clinical practice.
- Cost and Compliance Considerations:
The infrequent dosing schedule can enhance patient compliance—a critical factor in long-term risk reduction. These advantages, when combined with consistent LDL-C reduction, suggest that inclisiran could become a preferred therapeutic option in selected patient populations, particularly those with suboptimal responses to standard therapies.
- Real-World Applicability:
Ongoing studies in diverse regions (such as India and Korea) underscore the global applicability of inclisiran. As more outcome data become available, increasingly robust recommendations may be incorporated into guidelines issued by bodies such as the European Society of Cardiology (ESC) and National Cholesterol Education Program (NCEP).

Ongoing and Future Research

There remain several avenues for further investigation which will build upon the established foundation:

- Cardiovascular Outcome Trials:
While early exploratory analyses have shown encouraging trends regarding reductions in MACE, dedicated cardiovascular outcome trials such as ORION-4 (with a target enrollment of 15,000 patients) will definitively address whether the magnitude of LDL-C lowering translates into a lower incidence of cardiovascular events and mortality.
- Special Populations:
Ongoing trials in pediatric and adolescent populations (as seen in studies) are poised to answer critical questions regarding the safety and efficacy of inclisiran in patients with familial hypercholesterolemia from a young age. The results from these trials may eventually influence recommendations on early intervention in these high-risk groups.
- Combination and Comparative Therapies:
Additional studies comparing inclisiran with other lipid-lowering therapies (e.g., bempedoic acid in) and combination treatment strategies (such as adding pelacarsen on a background of inclisiran) aim to position inclisiran within the broader therapeutic armamentarium. These studies will help clinicians determine optimal combination regimens for patients who may require more aggressive therapy.
- Mechanistic and Pharmacoeconomic Analyses:
Further analyses of the molecular mechanisms underlying the long-term durability of inclisiran’s effect—as well as cost-effectiveness studies—are ongoing and will provide valuable data to support its use in healthcare systems worldwide. The unique mechanism, combined with infrequent dosing, may prove to be not only clinically advantageous but also cost-saving in the long run, which is crucial for widespread adoption in diverse healthcare settings.

Conclusion

In summary, a robust and multilayered clinical trial program has been conducted for inclisiran sodium, spanning early pharmacologic studies through expansive phase III trials and extending into post-marketing surveillance and real-world studies.

Starting with the ORION-1 trial, the early dose-escalation studies established the optimal dosing regimen, confirmed the potent and durable LDL-C and PCSK9 lowering effects, and demonstrated a favorable safety profile. Subsequently, the ORION-9, ORION-10, and ORION-11 phase III trials provided compelling evidence of approximately 50% LDL-C reductions in patients with familial hypercholesterolemia and ASCVD. These trials underscored not only the efficacy but also the safety, with injection site reactions being the only consistently reported adverse events. The studies have also expanded into special populations, including children and adolescents with familial hypercholesterolemia, as well as into various regional settings through post-marketing and real-world studies in India, Korea, and Latin America.

From the perspective of clinical applicability, inclisiran holds the promise of improved patient adherence given its twice-yearly dosing schedule, and it is expected to increasingly influence treatment guidelines as more cardiovascular outcome data become available. Furthermore, ongoing and future research will likely further delineate its role relative to other lipid-lowering agents, explore benefits in specific patient subgroups, and assess its long-term cardiovascular benefits.

The breadth of evidence, encompassing various trial phases and patient demographics, confirms that inclisiran sodium is not only effective in substantially reducing LDL-C levels but also offers a favorable safety profile with an operationally convenient dosing regimen. This multi-angle body of work provides the foundation for ongoing research and regulatory efforts that continue to refine and expand the role of inclisiran in the management of dyslipidemia.

In conclusion, the clinical trials conducted for inclisiran sodium represent a paradigm-shifting approach in dyslipidemia management. From early phase studies demonstrating the innovative mechanism of action to extensive phase III trials in diverse patient populations, the evidence supports the use of inclisiran as an effective, safe, and next-generation lipid-lowering therapy. Future research is set to further consolidate these findings and will likely drive broader clinical acceptance and integration into treatment guidelines for cardiovascular risk reduction.