P010. Evaluation of the Efficacy and Safety of AKCEA-TTR-LRx (ION-682884) in Patients with Transthyretin-mediated Amyloid Cardiomyopathy: The CARDIO-TTRansform Study

Background Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a fatal condition, leading to heart failure (HF) and ultimately death. ATTR-CM is caused by misfolding and aggregation of transthyretin (TTR), a protein produced by the liver. Depending on the presence or absence of a destabilizing mutation in the TTR gene, the disease can be classified as hereditary ATTR-CM (hATTR-CM) or wild-type ATTR-CM (wtATTR-CM), respectively. Despite the treatment with a TTR stabilizer, tafamidis, recently approved in the United States for the treatment of ATTR-CM, disease progression still occurs. AKCEA-TTR-LRX (ION-682884) is an antisense oligonucleotide (ASO) that inhibits the production of TTR. It has a similar design and sequence as inotersen (the parent compound), but is conjugated to a triantennary N-acetyl galactosamine (GalNAc3) moiety for selective receptor-mediated delivery to hepatocytes, the principal source of systemically circulating TTR. This delivery approach has yielded an up to 30-fold increase in potency and improved the safety and tolerability profiles of ASOs in human clinical trials. Conjugation of this ligand allows the use of a lower dose to achieve improved pharmacodynamic results. In a phase 1, randomized, placebo-controlled study, AKCEA-TTR-LRX given at a 45 mg, 60 mg or 90 mg dose, by subcutaneous (SC) injection every four weeks in 36 healthy volunteers achieved a mean pre-steady state reduction in serum TTR of 86%, 91% and 94%, respectively, compared to baseline. The dosage regimen of 45 mg SC every four weeks (27-fold lower exposure vs the inotersen dose in NEURO-TTR trial) was chosen for the pivotal phase 3 study. Methods CARDIO-TTRansform (ClinicalTrials.gov NCT04136171) is a Phase 3 global, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of AKCEA-TTR-L Rx in hATTR-CM or wtATTR-CM patients receiving available background standard of care (SoC) therapy. Approximately 750 patients around the world with a history of HF due to ATTR-CM will be randomized 1:1 to receive either AKCEA-TTR-LRx 45 mg or placebo administered by SC injection once every 4 weeks. Key inclusion criteria include diagnosis of ATTR-CM by biopsy or positive PYP/DPD/HMDP scan, interventricular septum thickness >12mm, NT-proBNP > 600 pg/mL, NYHA class I-III and 6-minute walk distance (6MWD) >150 m. Key exclusion criteria include, platelet count = 750 mg/g. Concomitant treatment with tafamidis as SoC for ATTR-CM is allowed. The study consists of a 120-week Treatment Period. Primary efficacy endpoint is the composite of cardiovascular (CV) mortality and recurrent CV clinical events at Week 120 study visit using the Andersen-Gill method. Secondary endpoints include the change from baseline in the 6MWD, KCCQ score, CV clinical events, CV death and all-cause of mortality at Week 120. Conclusions Despite recent advances, additional efficacious, safe and convenient treatment options for ATTR-CM are needed. The CARDIO-TTRansform trial is a large Phase 3 trial designed to evaluate the clinical efficacy and safety of AKCEA-TTR-LRx compared to placebo in patients with ATTR-CM receiving available SoC therapy.