Pelacarsen for Aortic Stenosis

Recruiting at 101 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Novartis Pharmaceuticals

Disqualifiers: Severe aortic stenosis, Uncontrolled hypertension, Malignancy, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the efficacy, safety and tolerability of pelacarsen (TQJ230) administered subcutaneously once monthly compared to placebo in slowing the progression of calcific aortic valve stenosis.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be optimally treated for existing cardiovascular risk factors, which might mean continuing certain medications.

What data supports the effectiveness of the drug Pelacarsen for aortic stenosis?

Research shows that Pelacarsen, also known as AKCEA-APO(a)-LRx, can significantly lower levels of lipoprotein(a) (Lp(a)), which is linked to cardiovascular disease and calcific aortic valve stenosis. In studies, Pelacarsen reduced Lp(a) levels by 35-80%, suggesting it may help slow the progression of aortic stenosis. ^{1 2 3 4 5}

How is the drug Pelacarsen unique in treating aortic stenosis?

Pelacarsen is unique because it specifically targets and lowers lipoprotein(a) levels, which are linked to aortic stenosis and cardiovascular disease, using antisense oligonucleotides (small pieces of DNA or RNA that can bind to specific molecules of RNA). This approach is novel as there are currently no FDA-approved drugs specifically designed to lower lipoprotein(a) levels. ^{2 3 6 7 8}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for men and women aged 50 or older with a blood level of Lipoprotein(a) at or above 125 nmol/L, as measured by the central lab. Participants should have mild to moderate calcific aortic valve stenosis but no other details are provided about who might be excluded.

Inclusion Criteria

I am between 50 and 79 years old.

My heart valve condition is not severe.

Lp(a) levels equal to or greater than 175 nmol/L at the screening visit, measured at the Central laboratory

Exclusion Criteria

I have had a major bleeding event or a stroke caused by bleeding.

I have a serious kidney condition.

I have severe narrowing of my heart's aortic valve due to calcium buildup.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pelacarsen (TQJ230) or placebo administered subcutaneously once monthly

36 months

36 visits (in-person, monthly)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Matching placebo (Drug)
• Pelacarsen (TQJ230) (Antisense Oligonucleotide)

Trial Overview The study tests Pelacarsen (TQJ230), given as a monthly subcutaneous injection, against a placebo to see if it can slow down the worsening of calcific aortic valve stenosis—a heart condition where the valve narrows and hardens.

Participant Groups

Group I: Pelacarsen (TQJ230) 80mg Experimental Treatment 1 Intervention

Pelacarsen (TQJ230) 80 mg prefilled syringe injected monthly, administered subcutaneously

Group II: Matching placebo Placebo Group 1 Intervention

Placebo to match pelacarsen (TQJ230) prefilled syringe injected monthly, administered subcutaneously

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

In patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI), serum apelin levels were significantly lower compared to age- and sex-matched controls, indicating a potential biomarker for the condition.

Post-TAVI, there was a significant increase in serum apelin levels and a decrease in pro-brain natriuretic peptide (Pro-BNP) levels, suggesting that TAVI not only improves heart function but also positively affects these biomarkers associated with heart stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Transcatheter Aortic Valve Implantation (TAVI) on Serum Apelin Levels in Patients with Aortic Valvular Stenosis. Kucukosmanoglu, M., Sahin, S., Urgun, OD., et al.[2021]

Lipoprotein (a) [Lp(a)] is a significant independent risk factor for cardiovascular diseases (CVD), and levels above 50 mg/dl are common in 20% of the population, particularly among those with CVD and aortic stenosis, indicating a need for targeted therapies.

The second generation antisense oligonucleotide (ASO) ISIS-APO(a)Rx has shown promising results in reducing Lp(a) levels by over 80% in both animal studies and a phase I human trial, suggesting it could be a potent treatment option for lowering CVD risk and slowing aortic stenosis progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans. Graham, MJ., Viney, N., Crooke, RM., et al.[2021]

Pelacarsen, an antisense oligonucleotide targeting the LPA gene, has been shown to safely and effectively reduce lipoprotein(a) levels by 35-80% in patients with cardiovascular disease, which is promising for managing cardiovascular risk in chronic kidney disease (CKD) patients.

However, the Phase 2 and upcoming Phase 3 trials exclude patients with significant kidney disease, limiting the understanding of pelacarsen's efficacy in CKD populations, where elevated Lp(a) levels are a concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease. Fernandez-Prado, R., Perez-Gomez, MV., Ortiz, A.[2023]

The study identified the binding characteristics and functional properties of the peptide (Pyr(1))Apelin-13 in human cardiovascular tissue, showing that it binds effectively to the APJ receptor with high affinity (K(D) values around 0.33-0.35 nM).

(Pyr(1))Apelin-13 was found to significantly contract human saphenous vein tissue, indicating its potential role in cardiovascular function, with a maximum contraction response of 22.6% compared to a strong potassium chloride solution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man. Katugampola, SD., Maguire, JJ., Matthewson, SR., et al.[2023]

ISIS-APO(a)Rx, a second-generation antisense drug, demonstrated significant dose-dependent reductions in plasma Lp(a) concentrations, achieving up to 77.8% decrease with the highest dose in a phase 1 study involving 47 participants.

The treatment was generally safe, with mild injection site reactions being the most common adverse event, supporting its potential as a therapeutic option for reducing cardiovascular disease risk associated with high Lp(a) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Tsimikas, S., Viney, NJ., Hughes, SG., et al.[2022]

Patients with high levels of lipoprotein(a) [Lp(a)] are at increased risk for serious cardiovascular diseases, but there are currently no FDA-approved treatments specifically targeting Lp(a).

Research is ongoing into pelacarsen as a potential therapy to lower Lp(a) levels, which may help reduce cardiovascular events in at-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of the Clinical Pharmacology of Pelacarsen: A Lipoprotein(a)-Lowering Agent. Hardy, J., Niman, S., Goldfaden, RF., et al.[2022]

The BASIK2 trial is investigating the effects of vitamin K2 (MK7) on calcification in patients with bicuspid aortic valve (BAV) and mild to moderate calcific aortic valve stenosis (CAVS), involving 44 subjects over an 18-month period.

The study aims to determine if MK7 supplementation can activate matrix Gla protein (MGP) to slow the progression of CAVS, with primary and secondary endpoints focused on changes in imaging measurements of calcification and heart function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design. Peeters, FECM., van Mourik, MJW., Meex, SJR., et al.[2022]

In a study involving hypercholesterolemic mice, pioglitazone (Pio) significantly reduced lipid deposition and calcification in the aortic valve, leading to improved valve function over a 6-month period.

Pio specifically targeted procalcific gene expression in the aortic valve, suggesting it may be an effective early intervention to prevent or slow the progression of calcific aortic valve stenosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone attenuates valvular calcification induced by hypercholesterolemia. Chu, Y., Lund, DD., Weiss, RM., et al.[2021]

References

1. Brazil pubmed.ncbi.nlm.nih.gov

The Impact of Transcatheter Aortic Valve Implantation (TAVI) on Serum Apelin Levels in Patients with Aortic Valvular Stenosis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease. [2023]

4. England pubmed.ncbi.nlm.nih.gov

[(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

A Review of the Clinical Pharmacology of Pelacarsen: A Lipoprotein(a)-Lowering Agent. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Pioglitazone attenuates valvular calcification induced by hypercholesterolemia. [2021]