Akcea Therapeutics and Ionis Pharmaceuticals announced the launch of a Phase 3 clinical trial evaluating the safety and efficacy of AKCEA-TTR-LRx (ION-682884) for the treatment of adults with familial amyloid polyneuropathy (FAP).
The global, open-label, randomized NEURO-TTRansform trial (NCT04136184) is expected to start in December. It is recruiting approximately 140 participants ages 18 to 82, diagnosed with stage 1 or 2 FAP, at the Ionis Investigative Site in Boston.
AKCEA-TTR-LRx is a second-generation RNA-targeted therapy in development for the treatment of all forms of transthyretin amyloidosis, including the hereditary (hATTR) and wild-type form of the disease (ATTRwt).
It works by preventing the RNA sequence of the TTR gene, which is defective in people with hATTR, from being translated into a protein. This reduces the buildup of abnormal amyloid deposits that accumulate in several tissues, slowly causing damage and eventually giving rise to symptoms associated with FAP or the other form of hATTR, called familial amyloid cardiomyopathy (FAC). Of note, RNA is the molecule that serves as the template for the production of a protein.
AKCEA-TTR-LRx was originally discovered by Ionis through its proprietary LIgand Conjugated Antisense (LICA) technology platform. It is now being co-developed by Ionis and its affiliate, Akcea.
NEURO-TTRansform will compare the effects of AKCEA-TTR-LRx to the placebo arm of a previous Phase 2/3 trial (NCT01737398), also sponsored by Ionis, that investigated the safety and efficacy of Tegsedi (inotersen) in people with FAP, compared with a placebo.
Once enrolled in NEURO-TTRansform, participants will be randomly assigned to receive subcutaneous (under-the-skin) injections of AKCEA-TTR-LRx every four weeks, or Tegsedi once a week. All study participants also will receive daily supplemental doses of the recommended daily allowance of vitamin A.
Those who are initially assigned to Tegsedi (20 out of the 140 expected to enroll), will cross over to AKCEA-TTR-LRx after 35 weeks.
The study’s main goals, which will be assessed at 66 weeks, include analyzing changes from the study’s start in the levels of TTR found in the serum, as well as changes in the scores of the modified Neuropathy Impairment Score +7 (mNIS+7) and of the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN).
The mNIS+7 is a measure of neurological impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function; the Norfolk QoL-DN evaluates the impact of neuropathy on individuals’ quality of life.
An interim analysis is planned at 35 weeks to assess changes from the study’s start in the levels of TTR found in the serum and in mNIS+7 scores.
Patients enrolled in NEURO-TTRansform will be followed for 85 weeks. After completing the study, they will have the option to enroll in an open-label extension study.
“The initiation of the TTRransform Phase 3 program represents an expansion of our dedication and commitment to the ATTR community. The NEURO-TTRansform study is the first of two Phase 3 studies that we expect to initiate with AKCEA-TTR-LRx. Our Phase 1 data are encouraging and we are excited about the possibility of delivering a significant advancement for people living with hATTR amyloidosis,” Damien McDevitt, PhD, Akcea’s interim CEO, said in a press release.
In a previous Phase 1 trial (NCT03728634) sponsored by Ionis, it was shown that monthly 90-mg injections of AKCEA-TTR-LRx could lower the levels of transthyretin (TTR), the protein involved in FAP, by up to 94% after 13 weeks of treatment in a group of healthy volunteers.
“The Phase 1 data of AKCEA-TTR-LRx are consistent with the clinical profile seen across our other LICA programs, highlighting the potential of LICA-engineered therapies to address both rare and more common diseases,” said Brett P. Monia, PhD, chief operating officer of Ionis.
“We remain dedicated to advancing this important clinical development program as rapidly as possible and are hopeful about the prospect of bringing a new safe and effective treatment to people living with the devastating symptoms of hATTR amyloidosis in the years ahead,” Monia added.
The company also launched the Phase 3 CARDIO-TTRansform clinical trial (NCT04136171), to test AKCEA-TTR-LRx in people with transthyretin‑mediated amyloid cardiomyopathy (ATTR CM), or FAC. The trial is not yet enrolling.