ALN-TTRsc02
Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic and life-threatening disease, caused by transthyretin (TTR) gene mutations. TTR is released by the liver and is an amyloidogenic protein that can lead to a heterogeneous class of disorders characterized by the accumulation of amyloid fibrils. As the discovery of RNA interference (RNAi) mechanisms, subcutaneously administered small interfering RNA (siRNA) with enhanced stability chemistry to target hepatic production of wide-type and mutant TTR proteins has been explored in the last decade. Recently, ALN-TTRsc02 (trade name: Vutrisiran) as a novel siRNA drug is designed as a treatment and is being developed for familial amyloid polyneuropathy (FAP) or other types of transthyretin amyloidosis.
Introduction to hATTR Amyloidosis
Figure 1. Clinical manifestations of hATTR amyloidosis. (Gertz, 2017)
hATTR amyloidosis is a rare, progressive disease featured by abnormal deposition of polypeptide amyloid fibrils in varying organs and tissues of the body. There're a wide diversity of clinical presentations for this multisystemic disorder, thereby it's usually subject to misdiagnosed or delayed diagnosis. Although the accurate prevalence is hard to determine, existing estimations suggest a worldwide prevalence of 50,000 patients, with various phenotypic presentations of the disease. Because of the heterogeneous nature of its presentations, incorrect or delayed diagnosis can severely affect the quality of life for these individuals. hATTR amyloidosis can result in significant disability, even mortality. After an exact diagnosis of hATTR amyloidosis, new patients should undergo appropriate and effective treatment as soon as possible. Accordingly, there is an unmet medical need for unique, effective, and safe therapies, such as siRNA-based therapeutic options.
ALN-TTRsc02 in Clinical Trials
ALN-TTRsc02 is an investigational GalNAc (N-acetylgalactosamine)-conjugated siRNA designed to suppress the synthesis of wild-type and mutant TTR proteins. The primary objective of current studies is to evaluate the safety and tolerability of this drug. Secondary objectives involve the assessment of the pharmacodynamic (PD) effect and the characterization of pharmacokinetics (PK) of ALN-TTRsc02. Specifically, PD refers to a drug's effect on the body, while PK refers to the body's effect on a drug. Several investigations have entered clinical trials, covering from Phase I to Phase III stage.
Figure 2. Therapeutic hypothesis. (Adams, 2019)
- Mechanism of action
Both hATTR and wide-type ATTR are fatal diseases. In patients, ALN-TTRsc02 drug targets faulty mRNAs, namely the intermediate messenger molecules between the TTR gene and TTR protein. By binding to TTR's mRNA, ALN-TTRsc02 initials a natural process called RNAi program to promote the destruction of mRNA molecules. The RNAi mechanism could prevent the production of the abnormal TTR proteins that may cause the disease for individuals.
- Clinical trials
In Phase I, a multi-center, randomized, and dose-dependent study of ALN-TTRsc02 has healthy volunteers up to 110. Between June 2016 and October 2017, 80 healthy volunteers (60 ALN-TTRsc02 and 20 Placebo) have been randomly divided into groups and treated with a concentration of 5, 25, 50, 100, 200, 300mg. As a result, ALN-TTRsc02 has been well-tolerated at all dose cohorts and there're no serious adverse events observed. Adverse events are mild or moderate, including redness and pain at the injected site, cough, nausea, itching, and abdominal pain. A single 25mg dose of ALN-TTRsc02 lowers the production of TTR proteins by up to 98.4% for more than 4 months, and a 50mg dose reduced it by 86.2%. Based on preliminary data, this siRNA-based agent exhibits significant TTR reduction that is maintained over an extended period.
As well, ALN-TTRsc02 is being researched in two Phase III clinical trials. The first is called HELIOS-A (NCT03759379), which is investigating ALN-TTRsc02 in hATTR (also known as FAP) patients. The trial has registered 160 participants, who will receive either 25mg subcutaneous injections of ALN-TTRsc02 once every 12 weeks. These patients will be evaluated at 6th and 18th months using multiple functional measurements. The trial is estimated to be completed by May 2024. The second Phase III trial is called HELIOS-B (NCT04153149) that is studying ALN-TTRsc02 in patients with TTR amyloidosis but also suffered cardiomyopathy. The participants will receive either 25mg subcutaneous injections of ALN-TTRsc02 every 3 weeks or a placebo. The number of cardiovascular-related hospitalizations and scores on functional assessments will be monitored and analyzed for participants for up to 36 months. The trial is still enrolling volunteers and is expected to conclude in June 2025.
Additionally, scientists have studied any influence the ALN-TTRsc02 had on the body by evaluating the levels of TTR protein and vitamin A in the blood. Safety measurements consist of vital signs, physical examinations, electrocardiograms, laboratory assessments, and adverse events monitoring. As a well-recognized specialist in siRNA-based therapeutics, Creative Biolabs always focuses on the newest advances of ALN-TTRsc02 research for hATTR amyloidosis on clinical trials. If you want to know more about gene therapy or siRNA custom services, please directly contact us or send an e-mail with your specific request.
References
- Gertz, M.A. (2017). Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 23(7 Suppl): S107-S112.
- Adams, D.; et al. (2019). Phase 1 study of ALN-TTRsc02, a subcutaneously administered investigational RNAi therapeutic for the treatment of transthyretin-mediated amyloidosis. Rev. Neurol. 175: S129.
