AKCEA-TTR-LRx Reduces Levels of TTR in Healthy Volunteers, Phase 1 Trial Shows

Akcea Therapeutics’ next-generation antisense medicine AKCEA-TTR-L_Rx (ION-682884) — currently in development for the treatment of all forms of familial amyloid polyneuropathy (FAP) — reduces the levels of a key FAP protein in healthy volunteers, a Phase 1 trial found.

Some participants saw a greater than 90% reduction in their levels of transthyretin (TTR), the protein involved in FAP, the results showed.

The trial’s findings were presented in a poster, “Phase 1 Investigation of a Ligand-Conjugated Antisense Oligonucleotide with Increased Potency for the Treatment of Transthyretin Amyloidosis,” at the Heart Failure Society of America (HFSA) 23rd Annual Scientific Meeting. HFSA 2019 was held Sept. 13-16 in Philadelphia.

FAP, also known as hereditary transthyretin amyloidosis, is a rare progressive disease normally caused by genetic mutations in the TTR gene, which provides instructions for making the transthyretin (TTR) protein.

The structure of transthyretin changes when mutations occur, preventing it from binding to other TTR proteins, as required for its normal function. Abnormal TTR protein can form amyloid deposits that accumulate in several tissues, slowly causing damage and eventually giving rise to symptoms associated with FAP.

Some people carrying no known genetic mutations in TTR may develop a different form of the disease, known as wild-type transthyretin amyloidosis.

AKCEA-TTR-L_Rx is a second-generation RNA-targeted therapy now in development for the treatment of all forms of transthyretin amyloidosis, including the hereditary and wild-type form of the disease.

It works by preventing the RNA sequence of the TTR gene from being translated into a protein. That reduces the build-up of abnormal amyloid deposits in tissues. RNA is the molecule that serves as the template for the production of a protein.

AKCEA-TTR-L_Rx was originally discovered by Ionis Pharmaceuticals through its proprietary LIgand Conjugated Antisense (LICA) technology platform. It is now being co-developed by Ionis and its affiliate, Akcea Therapeutics.

Safety, tolerably, and chemical properties of AKCEA-TTR-L_Rx are being assessed in an ongoing double-blind, placebo-controlled, dose-escalation, Phase 1/2 clinical trial (NCT03728634) sponsored by Ionis. The trial is still recruiting participants in Canada. Find more information here.

The goal of the first part of the study (Phase 1) was to evaluate the effects of increasing doses of AKCEA-TTR-L_Rx on the levels of TTR protein in a group of healthy volunteers.

After enrollment, study participants were randomly assigned to receive either AKCEA-TTR-L_Rx or a placebo through under-the-skin injections, once every four weeks, for a total treatment period of 13 weeks. This was followed by an additional assessment period of 13 weeks, during which volunteers did not receive any further treatment.

The Phase 1 study revealed that:

• injections of AKCEA-TTR-L_Rx at a dose of 45 mg per month could induce a mean reduction of 86% in TTR levels after 13 weeks of treatment
• injections of the medicine at a dose of 90 mg per month could induce a mean reduction in TTR levels of 94% after 13 weeks of treatment
• a single injection of AKCEA-TTR-L_Rx at a maximum dose of 120 mg per month induced a mean reduction of 86% in TTR levels after four weeks

In general, the treatment was shown to be well-tolerated, with all reported adverse effects being mild in severity, with the exception of one case of moderate headache. None of the adverse events required volunteers to stop treatment prematurely.

“The Phase 1 data demonstrate an impressive and meaningful reduction in the TTR protein while maintaining a positive safety and tolerability profile with monthly administration of AKCEA-TTR-L_Rx,” Louis O’Dea, chief medical officer at Akcea Therapeutics, said in a press release. “These results are encouraging as we expand our commitment to the TTR amyloidosis community through development of AKCEA-TTR-L_Rx for patients with both hereditary and wild type forms of ATTR amyloidosis,”

“Our goal is to improve patients’ lives with a safe and efficacious therapy that targets and reduces TTR protein at its source. The convenience of monthly administration would also represent a significant advantage for patients living with this debilitating and fatal disease,” he added.

Akcea and Ionis are planning to launch the Phase 3 program for AKCEA-TTR-L_Rx later this year.