ALN-AT3SC
Hemophilia is a rare, inherited bleeding disease, occurring when blood clotting factors are faulty or missing. It almost has an impact on males. The burden of disorder for individuals with hemophilia is high, especially in those who develop inhibitors. Fortunately, small interfering RNAs (siRNAs) can be delivered to cells either endogenously as gene-encoding siRNAs or exogenously as synthetic agents. Recent research demonstrates the general application of siRNAs to silence gene expression in a variety of cell types and whole mammals via RNA interference (RNAi) process. Besides their value for dissecting gene functions and validating specific targets, siRNAs also hold great potential as a treatment for gene therapy. ALN-AT3SC (trade name: Fitusiran), is an RNAi therapy, represents a novel mechanism to treat patients with hemophilia, and in those with inhibitors, offers a more rapid, simple, and efficacious bypass candidate than currently available.
Introduction to Hemophilia
Hemophilia is an X-linked bleeding disorder that results from a deficiency of coagulation factor VIII (FVIII), for hemophilia A (HA), or a deficiency of coagulation factor IX (FIX), for hemophilia B (HB). Type A is known as classic hemophilia, while type B hemophilia is named Christmas disease. Clotting factor mutations lead to clinical bleeding, spontaneous or traumatic, primarily in joints and muscles. Recurrent bleeding into joints will cause high morbidity, with chronic arthritis, pain, and disability. This disorder can be observed in all races and ethnic types. Hemophilia A is more common than hemophilia B, with a prevalence of 1 in 5,000 to 1,0000 male live births compared to 1 in 25,000 to 30,000, respectively. Although hemophilia is generally diagnosed at birth, this disorder could be acquired later in life if the body starts to produce antibodies that destroy clotting factors. The acquired type of hemophilia is very rare, which is also called acquired hemophilia A or autoimmune hemophilia.
Figure 1. Comparison of characteristics of hemophilia A and B. (Castaman, 2019)
ALN-AT3SC in Clinical Trials
The current standard of care to prevent hemophilia-caused bleeding is through prophylactic intravenous infusion of concentrated clotting factors many times per week. However, treatment with factor products is costly and quality-of-life of patients is reduced. A key step for the development of siRNA-based therapeutic agent for individuals with hemophilia is the identification of a proper target. Pro- and antithrombotic factors expressed within the coagulation system tightly control the generation of thrombin. ALN-AT3SC, also known as ALN-AT3 or SAR-439774, is an investigational RNAi therapeutic targeting antithrombin (AT, encoded by SERPINC1), and has been developed to address limitations of conventional treatments.
Figure 2. Site of action of fitusiran on coagulation cascade. (Machin, 2018)
- Mechanism of action
ALN-AT3SC is a siRNA agent designed to target AT mRNA in the liver and interfere with mRNA translation by binding to and degrading AT mRNA to block its synthesis, and thereby facilitate hemostasis. In preclinical studies, AT knockdown exhibited a strong response in mice and nonhuman primates. From this evidence, AT knockdown resulted in a dose-dependent decrease of AT levels, which is associated with a dose-dependent increase in thrombin production and a reduction in bleeding. In terms of animal models and in vivo tail clip assays, it was illustrated that achieving a >50% decrease in AT levels was hemostatic and may predictably decline the bleeding phenotype in hemophilia patients. ALN-AT3SC targets hepatocytes by conjugation of N-acetylgalactosamine (GalNAc), as well as the site of synthesis and secretion of AT into the circulation. It was an ideal approach to accomplish prophylaxis, in subjects with hemophilia by a simpler subcutaneous mode of dosing with a prolonged duration of action.
- Clinical trials
ALN-AT3SC has been evaluated in patients with hemophilia (complicated by inhibitors or no inhibitors) in Phase I and II trials and is currently under assessment in Phase III clinical trials. A Phase I, open-label dose-escalation trial of ALN-AT3SC was performed in 4 healthy volunteers and 30 patients with hemophilia A or hemophilia B. In healthy groups, a single subcutaneous dose of ALN-AT3SC gave rise to maximum AT lowering (~19%) by day 21, and AT recovery into the normal scope by day 56. Alternate dosing managements were evaluated in hemophilia patients with weekly and monthly dosing. A fixed-dose of ALN-AT3SC 80 mg per month was shown to complete a mean maximum AT lowering of 87%. The connection between AT decreased and increased thrombin generation was also confirmed and demonstrated to be similar between individuals with hemophilia A and B. Up to now, ALN-AT3SC is likely to be a potential therapy for hemophilia patients.
Tab.1 Fitusiran for hemophilia A and B. (Machin, 2018)
The RNAi specificity makes it attractive for therapeutic application in rare/orphan diseases, including hemophilia. Today, lipid-based nanoparticle formulations have solved several remaining problems in cellular targeting and delivery, such as siRNA instability, limited cell uptake, and pharmacokinetics (PK) issues. The availability of novel therapeutics, in particular siRNA directing AT for those with hemophilia, has the opportunity to reduce bleeding and the burden of treatment, and to improve quality-of-life. 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
- Castaman, G.; et al. (2019). Hemophilia A and B: molecular and clinical similarities and differences. Haematologica. 104(9): 1702-1709.
- Machin, N.; et al. (2018). An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. J Blood Med. 9: 135-140.
