In the Journals

Novel drug reduces lipids in patients with elevated triglycerides

Sotiros Tsimikas
Sotiros Tsimikas

An N-acetylgalactosamine-conjugated antisense oligonucleotide safely improved the atherogenic lipid profile of patients with modest elevations in triglyceride levels, according to a study published in the European Heart Journal.

“This could be a fantastic drug to treat an unmet need that’s still out there, which is in patients who have high triglyceride levels —150 mg/dL to 200 mg/dL — that have high remnant cholesterol,” Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, vice president of global cardiovascular development at Ionis Pharmaceuticals, which is affiliated with Akcea, and professor of medicine and director of vascular medicine at University of California, San Diego School of Medicine, told Cardiology Today.

In this phase 1/2a study, Veronica J. Alexander, PhD, of Ionis Pharmaceuticals, and colleagues analyzed data from 67 patients aged 18 to 65 years with triglyceride levels of at least 90 mg/dL or 200 mg/dL. Patients were assigned a single dose (10 mg, 30 mg, 60 mg, 90 mg or 120 mg), a 15-mg or 30-mg dose per week for 6 weeks or 60 mg every 4 weeks for 3 months of an N-acetylgalactosamine-conjugated antisense oligonucleotide (AKCEA-APOCIII-LRx, Akcea Therapeutics/Ionis/Novartis).

“This drug represents a relatively new and emerging technology, which is the drug itself targeting [apolipoprotein C-III],” Tsimikas said in an interview. “It is specifically designed to accumulate or go to the liver where most of the ApoC-III is made by having this N-acetylgalactosamine-conjugated antisense oligonucleotide.”

In the single-ascending dose group, the median reductions in ApoC-III 14 days after dosing were 0% for the 10-mg dose, –42% for the 30-mg dose, –73% for the 60-mg dose, –81% for the 90-mg dose and –92% for the 120-mg dose. There were also reductions triglycerides 14 days after dosing (–12%, –7%, –42%, –73% and –77%, respectively).

Veronica J. Alexander
Veronica J. Alexander

At 1 week after the last dose, the median reductions in ApoC-III were –66% for patients assigned 15 mg per week, –84% for those assigned 30 mg per week and –89% for patients assigned 60 mg every 4 weeks. Median reductions in triglycerides were –59%, –73% and –66%, respectively.

An N-acetylgalactosamine-conjugated antisense oligonucleotide safely improved the atherogenic lipid profile of patients with modest elevations in triglyceride levels, according to a study published in the European Heart Journal.
Source: Adobe Stock

“It gives you very high potency for lowering ApoC-III and, therefore, triglycerides so that you can actually give much lower doses to get similar efficacy as prior compounds that did not have this N-acetylgalactosamine modification,” Tsimikas said in an interview.

All dose groups had significant reductions in ApoB, total cholesterol, VLDL cholesterol and non-HDL and increases in HDL.

One patient assigned 15 mg per week had an injection site reaction of mild erythema after the third injection. There were no platelet count reductions, influenza-like symptoms or renal and liver safety signals in all patients.

“Overall, these are very good characteristics for going forward for new trials,” Tsimikas told Cardiology Today. – by Darlene Dobkowski

For more information:

Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, can be reached at University of California San Diego Health - La Jolla, 9434 Medical Center Drive, La Jolla, CA 92037; email: stsimikas@ucsd.edu.

Disclosures: The study was supported by Ionis Pharmaceuticals. Tsimikas reports he is an employee of Ionis Pharmaceuticals, a co-inventor who receives royalties from patents owned by the University of California, San Diego, on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins, co-founder of Oxitope and is a consultant for Boston Heart Diagnostics. Please see the study for all other authors’ relevant financial disclosures.

 

Sotiros Tsimikas
Sotiros Tsimikas

An N-acetylgalactosamine-conjugated antisense oligonucleotide safely improved the atherogenic lipid profile of patients with modest elevations in triglyceride levels, according to a study published in the European Heart Journal.

“This could be a fantastic drug to treat an unmet need that’s still out there, which is in patients who have high triglyceride levels —150 mg/dL to 200 mg/dL — that have high remnant cholesterol,” Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, vice president of global cardiovascular development at Ionis Pharmaceuticals, which is affiliated with Akcea, and professor of medicine and director of vascular medicine at University of California, San Diego School of Medicine, told Cardiology Today.

In this phase 1/2a study, Veronica J. Alexander, PhD, of Ionis Pharmaceuticals, and colleagues analyzed data from 67 patients aged 18 to 65 years with triglyceride levels of at least 90 mg/dL or 200 mg/dL. Patients were assigned a single dose (10 mg, 30 mg, 60 mg, 90 mg or 120 mg), a 15-mg or 30-mg dose per week for 6 weeks or 60 mg every 4 weeks for 3 months of an N-acetylgalactosamine-conjugated antisense oligonucleotide (AKCEA-APOCIII-LRx, Akcea Therapeutics/Ionis/Novartis).

“This drug represents a relatively new and emerging technology, which is the drug itself targeting [apolipoprotein C-III],” Tsimikas said in an interview. “It is specifically designed to accumulate or go to the liver where most of the ApoC-III is made by having this N-acetylgalactosamine-conjugated antisense oligonucleotide.”

In the single-ascending dose group, the median reductions in ApoC-III 14 days after dosing were 0% for the 10-mg dose, –42% for the 30-mg dose, –73% for the 60-mg dose, –81% for the 90-mg dose and –92% for the 120-mg dose. There were also reductions triglycerides 14 days after dosing (–12%, –7%, –42%, –73% and –77%, respectively).

Veronica J. Alexander
Veronica J. Alexander

At 1 week after the last dose, the median reductions in ApoC-III were –66% for patients assigned 15 mg per week, –84% for those assigned 30 mg per week and –89% for patients assigned 60 mg every 4 weeks. Median reductions in triglycerides were –59%, –73% and –66%, respectively.

An N-acetylgalactosamine-conjugated antisense oligonucleotide safely improved the atherogenic lipid profile of patients with modest elevations in triglyceride levels, according to a study published in the European Heart Journal.
Source: Adobe Stock

“It gives you very high potency for lowering ApoC-III and, therefore, triglycerides so that you can actually give much lower doses to get similar efficacy as prior compounds that did not have this N-acetylgalactosamine modification,” Tsimikas said in an interview.

All dose groups had significant reductions in ApoB, total cholesterol, VLDL cholesterol and non-HDL and increases in HDL.

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One patient assigned 15 mg per week had an injection site reaction of mild erythema after the third injection. There were no platelet count reductions, influenza-like symptoms or renal and liver safety signals in all patients.

“Overall, these are very good characteristics for going forward for new trials,” Tsimikas told Cardiology Today. – by Darlene Dobkowski

For more information:

Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, can be reached at University of California San Diego Health - La Jolla, 9434 Medical Center Drive, La Jolla, CA 92037; email: stsimikas@ucsd.edu.

Disclosures: The study was supported by Ionis Pharmaceuticals. Tsimikas reports he is an employee of Ionis Pharmaceuticals, a co-inventor who receives royalties from patents owned by the University of California, San Diego, on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins, co-founder of Oxitope and is a consultant for Boston Heart Diagnostics. Please see the study for all other authors’ relevant financial disclosures.