Antisense oligonucleotide improves lipid profile in high triglycerides

Veronica J. Alexander

Patients with triglyceride levels greater than 200 mg/dL treated with a GalNAc conjugated second-generation antisense oligonucleotide had an improved atherogenic lipid profile and the potential for less frequent dosing, according to data presented at the American College of Cardiology Scientific Session.

Perspective from Michael H. Davidson, MD

In this phase 1/2a study, Veronica J. Alexander, PhD, of Ionis Pharmaceuticals, and colleagues analyzed data from patients aged 18 to 65 years with triglyceride levels greater than 200 mg/dL. Patients in the five single-ascending dose cohorts received sequential doses of the antisense oligonucleotide (AKCEA-APOCIII-L_Rx, Akcea Therapeutics/Ionis/Novartis) subcutaneously: 10 mg, 30 mg, 60 mg, 90 mg and 120 mg. The three multiple-ascending dose cohorts were given 15 mg and 30 mg of the drug per week for 6 weeks, and one group received 60 mg of the antisense oligonucleotide every 4 weeks for 3 months.

“The AKCEA-APOCIII-L_Rx is an antisense oligonucleotide that specifically targets the ApoC-III messenger RNA and prevents the production of ApoC-III protein,” Alexander said during the presentation.

At 14 days, patients in the single-ascending dose cohorts who received 10 mg, 30 mg, 60 mg, 90 mg and 120 mg of the antisense oligonucleotide had significant reductions in apolipoprotein C-III (–4%, –32%, –65%, –78% and –91%, respectively) and triglycerides (–12%, –11%, –43%, –68% and –77%, respectively).

One week after the last dose, patients in the multiple-ascending dose cohorts who received 15 mg, 30 mg and 60 mg of the treatment also had significant triglyceride (–61%, –71% and –65%, respectively) and ApoC-III reductions (–65%, –84% and –83%, respectively). ApoB decreased by up to approximately 30% and HDL increased by up to approximately 100%, according to the abstract.

For approximately 90 days after the last dose, decreased ApoC-III levels remained reduced by up to 50%.

The treatment was well-tolerated by patients, and adverse effects such as influenza-like reactions, injection-site reactions, platelet reductions and renal adverse events were not seen, according to the researchers.

“Based on the encouraging tolerability and safety profile, we have started a phase 2 study in patients with [triglycerides] greater than 200 mg/dL with cardiovascular disease,” Alexander said during the presentation. – by Darlene Dobkowski

Reference:

Alexander VJ, et al. Abstract 1140M-05. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.

Disclosure: Alexander is an employee of Ionis Pharmaceuticals.

Perspective

Michael H. Davidson, MD

The major takeaway is that volanesorsen (Akcea), which is going to be ready for FDA approval hopefully in August, is very effective, but it’s a high dose and there are more potential side effects. Seeing the efficacy in this more broader population, which could have the probability of having what looks like a potentially really good safety profile, could make a really big difference in how this therapy could be used in a wider population.

We’ll need to see a phase 2 study, because with repeated injections over time, whether some of the safety issues that came up with the higher doses maybe turn up here. It’s important to look at longer-term safety.

Michael H. Davidson, MD

Cardiology Today Editorial Board Member

University of Chicago Pritzker School of Medicine

Disclosures: Davidson reports he consults for Akcea.