Inclisiran
- Generic Name
- Inclisiran
- Brand Names
- Leqvio
- Drug Type
- Biotech
- CAS Number
- 1639324-58-5
- Unique Ingredient Identifier
- UOW2C71PG5
- Background
Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol. Lowering circulating plasma LDL-C levels offers an additional benefit of reducing the risk of cardiovascular disease (CVD) and improving cardiovascular outcomes, as hypercholesterolemia is a major known risk factor for CVD.
On December 11, 2020, the European Commission (EC) granted authorization for marketing inclisiran as the first and only approved siRNA for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, alone or in combination with other lipid-lowering therapies. Inclisiran was later approved by the FDA on December 22, 2021, for the treatment of heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease in adults. It is marketed under the trade name Leqvio.
- Indication
In Europe, inclisiran is indicated for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia in adults, as an adjunct to diet. It can be used in combination with a statin or statin with other lipid-lowering therapies in patients who cannot reach LDL-C goals with the maximum tolerated dose of a statin. In patients who cannot tolerate statins or in whom a statin is contraindicated, inclisiran can be used as monotherapy or in combination with other lipid-lowering therapies.
In the US, inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of lowdensity lipoprotein cholesterol (LDL-C).
- Associated Conditions
- Atherosclerotic Cardiovascular Diseases, Heterozygous Familial Hypercholesterolemia (HeFH), Mixed Dyslipidemias, Primary Hypercholesterolemia
LEQVIO Emerges as Leading PCSK9 Inhibitor in Cholesterol Management Across Major Markets
• Novartis's LEQVIO (inclisiran), the first FDA-approved siRNA therapy for LDL-C reduction, is projected to reach USD 2.2 billion in US market size by 2034, offering a novel mechanism with biannual dosing that enhances patient adherence.
• The PCSK9 inhibitor market, valued at USD 2 billion across seven major markets in 2023, is expected to grow substantially due to expanding applications in statin-intolerant patients and preventive cardiovascular strategies.
• Emerging competitors including Lerodalcibep, Merck's oral MK-0616, and Verve Therapeutics' gene-editing candidates are advancing through clinical trials, potentially disrupting LEQVIO's market position after 2027.
Federal Court Dismisses Sanofi's Appeal, Orders Amgen's Repatha Patent Applications to Proceed in Australia
• The Federal Court of Australia has dismissed Sanofi's appeal against Amgen's PCSK9 antibody patents, ordering that Amgen's Repatha patent applications proceed to grant under Australia's pre-2013 patent laws.
• This Australian ruling contrasts with decisions in the US, where the Supreme Court invalidated similar Amgen patents for lack of enablement, highlighting significant jurisdictional differences in antibody patent protection.
• The case provides important precedent for other valuable antibody patents approaching the end of their term that are still subject to Australia's old Patent Act as biosimilars seek market entry.
Verve Therapeutics Expands Base Editing Trial for Cholesterol Treatment into US Following FDA Clearance
• Verve Therapeutics received FDA clearance to expand its VERVE-102 trial into the US, potentially offering a one-time base editing treatment for persistent high cholesterol conditions.
• The company's gene editing approach targets the PCSK9 gene to deliver lifelong cholesterol lowering, distinguishing it from current therapies that require regular injections ranging from bi-weekly to semi-annually.
• Initial safety and efficacy data from the Phase 1b Heart-2 trial is expected by the end of June, with dose escalation data and Phase 2 trial initiation planned for later this year.
AstraZeneca's Oral PCSK9 Inhibitor Shows Promise in Phase 1 Trial
• AstraZeneca's oral PCSK9 inhibitor, AZD0780, demonstrated a 52% reduction in LDL cholesterol when added to statin therapy in a Phase 1 trial.
• The study included treatment-naive participants with hypercholesterolemia, showing a 78% total reduction from baseline in LDL-C levels.
• AZD0780's efficacy appears comparable to injectable PCSK9 inhibitors, with the added convenience of oral administration, unaffected by food intake.
• AstraZeneca plans to advance AZD0780 into a Phase 2 program, joining MSD in the race to provide oral alternatives to injectable cholesterol-lowering drugs.
Madrigal's Rezdiffra Shows Promise in MASH Cirrhosis with Two-Year Data
• Madrigal Pharmaceuticals reports Rezdiffra (resmetirom) demonstrates potential benefits in patients with compensated MASH cirrhosis (F4c).
• Two-year data from the MAESTRO-NAFLD-1 trial shows a mean 6.7 kPa reduction in liver stiffness, the largest reported in this patient group.
• 51% of patients achieved a ≥25% reduction in liver stiffness, associated with reduced progression to end-stage liver disease.
• Rezdiffra's safety profile remains consistent, supporting its potential as a treatment for F2-F4c MASH pending further trial outcomes.
Verve Therapeutics Advances Pipeline with Focus on Gene Editing for Cardiovascular Disease
• Verve Therapeutics anticipates initial data from the Heart-2 Phase 1b trial of VERVE-102, targeting PCSK9, in Q2 2025, including safety and efficacy data.
• VERVE-301 has been nominated as the development candidate targeting the LPA gene, triggering a milestone payment from Eli Lilly, who will fund Phase 1 development.
• The Pulse-1 Phase 1b trial for VERVE-201, which targets ANGPTL3, is progressing, with an update expected in the second half of 2025.
• Verve's strong financial position, boosted by the Lilly milestone payment, extends the company's cash runway into mid-2027.
Homozygous Familial Hypercholesterolemia Treatment Market to Surge by 2034
The Homozygous Familial Hypercholesterolemia (HoFH) treatment market, valued at approximately USD 108 million in 2022, is expected to grow significantly by 2034. With key players like Arrowhead Pharmaceutical and Novartis leading the charge, the market is set to benefit from increased disease prevalence, awareness, and the launch of innovative therapies. The FDA's recent approval of Evkeeza for children marks a pivotal advancement in HoFH treatment.
Novartis' Intrathecal Zolgensma Shows Positive Phase III Results for SMA Type 2
• Novartis' intrathecal onasemnogene abeparvovec (OAV101 IT) met its primary endpoint in the Phase III STEER study for SMA Type 2.
• The STEER trial demonstrated a statistically significant increase in motor function, as measured by HFMSE scores, in treatment-naïve patients.
• OAV101 IT showed a favorable safety profile, with adverse events similar to the control arm, potentially expanding treatment options for SMA.
• Novartis plans to submit the data to regulatory agencies in 2025, seeking approval to broaden the availability of this one-time gene therapy.
RNA Therapy Market Set to Reach $4.16 Billion by 2034 as Clinical Trials Accelerate
• The global RNA therapy clinical trials market is projected to grow from $2.85 billion in 2024 to $4.16 billion by 2034, with a CAGR of 3.85%, driven by advancements in mRNA, siRNA, and antisense oligonucleotide-based therapies.
• Over 80 companies are currently evaluating more than 100 RNA therapies across various development stages, with significant activity in rare diseases, oncology, and genetic disorders.
• Recent breakthroughs include FDA clearance for the first CRISPR/Cas13 RNA-editing therapy for neovascular age-related macular degeneration and promising results for RNA therapies targeting rare muscular dystrophies.
FDA Accepts Alnylam's Vutrisiran Application for ATTR Amyloidosis with Cardiomyopathy
• The FDA has accepted Alnylam's sNDA for vutrisiran to treat ATTR amyloidosis with cardiomyopathy, setting a PDUFA date of March 23, 2025.
• The application is based on Phase 3 HELIOS-B trial results, which demonstrated favorable cardiovascular outcomes and improved survival in ATTR-CM patients.
• If approved, vutrisiran would be the first treatment for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis in the U.S.
• Vutrisiran's sNDA acceptance signifies a major advancement for Alnylam, potentially expanding the drug's market and solidifying its position in the ATTR space.
Acoramidis Gains Global Momentum: FDA Approval, EU Recommendation, and Promising Clinical Data
• Acoramidis (Attruby), developed by Stanford Medicine and BridgeBio, receives FDA approval for transthyretin amyloid cardiomyopathy (ATTR-CM) treatment, marking a significant milestone.
• The European Medicines Agency's CHMP recommends acoramidis for EU marketing authorization based on positive Phase 3 ATTRibute-CM trial results.
• Clinical trials demonstrate acoramidis' efficacy in reducing cardiovascular-related hospitalizations and improving survival rates for ATTR-CM patients.
• Bayer and BridgeBio collaborate to commercialize acoramidis, with Bayer holding EU rights and plans for a launch in Europe in early 2025.
Inclisiran Demonstrates Efficacy and Improved Adherence in Reducing LDL-C
• Inclisiran, with its twice-yearly dosing, shows significant promise in improving patient adherence to LDL-C-lowering therapy, crucial for managing ASCVD.
• Clinical trials (ORION-10, ORION-11, ORION-8) confirm inclisiran's efficacy in reducing LDL-C levels, with a substantial percentage of patients achieving target levels.
• Real-world data from the V-INITIATE trial and US claims databases support inclisiran's consistent efficacy and superior adherence compared to standard care and other therapies.
• Inclisiran's unique mechanism of action, targeting PCSK9 protein formation in the liver, contributes to its prolonged duration of effect and convenient dosing schedule.
Pharma Giants Report Q3 Earnings: Merck, Pfizer, AbbVie, and Novartis Lead with Key Drug Updates
• Merck's Keytruda sales surged 17% due to strong uptake in earlier-stage indications, while a new Phase III trial for a personalized mRNA cancer vaccine in NSCLC was initiated.
• Pfizer's Q3 revenues increased by 32%, driven by non-COVID products and Seagen acquisitions, leading to raised 2024 earnings and revenue expectations.
• AbbVie's Rinvoq and Skyrizi sales rose significantly due to label expansions, and the company is set to acquire Aliada for $1.4 billion to bolster its neuroscience pipeline.
• Novartis' Scemblix received FDA approval for first-line Ph+ CML-CP, potentially quadrupling the eligible patient population, and the company raised its 2024 financial outlook.
Vutrisiran Shows Promise in ATTR-CM Treatment: Alnylam's HELIOS-B Data Highlights Cardiac Benefits
• New data from the HELIOS-B study reveals vutrisiran significantly improves cardiac structure and function in ATTR-CM patients over 30 months compared to placebo.
• Vutrisiran demonstrates stability in cardiac biomarkers NT-proBNP and Troponin-I, indicating a potential disease-modifying effect, particularly when administered early.
• Alnylam has submitted regulatory applications to the FDA and EMA for vutrisiran, aiming to establish it as a first-line therapy for ATTR amyloidosis with cardiomyopathy.
• The HELIOS-B trial's results, published in NEJM, underscore vutrisiran's potential to reduce mortality and cardiovascular events in ATTR-CM patients.
Gilead's Lenacapavir Achieves 100% Efficacy in HIV Prevention Trial
• Gilead Sciences' lenacapavir, a twice-yearly injectable medication, demonstrated 100% efficacy in preventing HIV among cisgender women in Phase 3 trials.
• This breakthrough surpasses the efficacy of daily oral medications like Truvada and Descovy, marking a significant advancement in HIV prevention strategies.
• The study's findings could transform the landscape of HIV prevention, offering a more convenient and highly effective alternative for at-risk populations.
Inclisiran Demonstrates Significant LDL-C Lowering in V-MONO Trial
• Inclisiran monotherapy significantly reduced LDL-C levels compared to placebo and ezetimibe in patients with low to moderate ASCVD risk.
• The Phase III V-MONO study met its primary endpoints, showcasing inclisiran's superiority in LDL-C reduction.
• Novartis plans to present the V-MONO trial results to regulatory agencies, including the FDA, for potential label expansion.
• The V-MONO trial is part of the larger VictORION program, which includes over 60,000 patients across more than 30 trials.
NHS Pioneers Early Access to Amgen's Breakthrough KRAS Lung Cancer Drug Lumykras
• The MHRA has approved Lumykras (sotorasib) for previously treated advanced NSCLC with KRAS G12C mutation, making Britain the first in Europe to offer this groundbreaking treatment.
• In clinical trials, Lumykras demonstrated significant efficacy with a 37.1% response rate and disease control in 80.6% of patients, marking a major advancement in targeting the previously "undruggable" KRAS mutation.
• The NHS will begin offering Lumykras to approximately 600 eligible lung cancer patients in England within weeks, through an early access agreement while NICE conducts cost-effectiveness evaluation.
Scottish Health Authority Rejects Daiichi Sankyo's Novel Cholesterol Drug Nilemdo
• The Scottish Medicines Consortium has declined to recommend Daiichi Sankyo's Nilemdo (bempedoic acid) for NHS Scotland, citing insufficient robustness in clinical and economic analyses.
• Nilemdo, approved by EMA and FDA for patients with high cholesterol who can't tolerate statins, launched in Germany with UK rollout planned for early next year.
• The rejection could impact the drug's projected $3 billion peak sales potential, especially if other health technology assessment agencies follow Scotland's decision.
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