RNA interference - great hopes in the fight against hemophilia
Alnylam Pharmaceuticals, a leading company in the development of therapeutic approaches based on the phenomenon of RNA interference (RNAi), has published promising results of preclinical studies of the drug ALN-AT3, intended for the treatment of hemophilia and rare diseases of the blood coagulation system by reducing the level of antithrombin in the blood. (Antithrombin is a protein that inhibits blood clotting and prevents thrombosis in the bloodstream.)
The results of the studies showed that both multiple and single subcutaneous administration of ALN-AT3 provides dose-dependent prolonged inactivation of plasma antithrombin in wild-type mice, mouse model of hemophilia A and primates. With laser damage to capillaries and bleeding from the subcutaneous vein of the leg in a mouse model of hemophilia A, subcutaneous administration of ALN-AT3 provided hemostatic protection comparable or even superior in effectiveness to the results of intravenous replacement therapy with blood clotting factor VIII, absent in this form of the disease.
Moreover, repeated administration of ALN-AT3 to wild-type mice resulted in a powerful, titratable and reversible inactivation of plasma antithrombin.
In addition, a series of experiments were conducted on primates with an "inhibitory" model of hemophilia, in which the phenotype of the disease was caused by the introduction of polyclonal antibodies to blood clotting factor VIII. In animals treated with ALN-AT3, a dose-dependent increase in thrombin synthesis was recorded, which ensured the restoration of hemostatic parameters to normal levels.
In general, the results obtained indicate that ALN-AT3 provides normalization of thrombin synthesis both in the absence of a sufficient amount of blood clotting factor VIII and in the presence of antibodies inactivating this factor.
Studies on the tolerability of the experimental drug have also brought very encouraging results. Thus, the weekly administration of excessively high doses of ALN-AT3 (10, 30 and 100 mg / kg body weight) in a mouse model of hemophilia A for 7 weeks, providing almost complete activation of antithrombin, did not lead to toxicologically significant changes recorded in clinical and pathoanatomic studies. In particular, there were no signs of thrombosis of blood vessels.
To study the long-term toxicity of the drug, a 26-week study was conducted on a mouse model of hemophilia A. In this case, all dosages of ALN-AT3 were also well tolerated by all animals in which no negative clinical manifestations were recorded. Moreover, compared with placebo, the experimental drug significantly improved the survival of animals, which confirms the hypothesis that a decrease in the level of antithrombin in the blood relieves the symptoms of the disease.
Alnylam is currently conducting a phase I clinical trial of ALN-AT3. As part of the already completed Part A, which was a double-blind, single-dose study conducted under placebo control, healthy volunteers were given a single subcutaneous injection of the drug at a dose of 30 mcg / kg of body weight. The currently ongoing Part B is an open dose escalation multidose study, which will involve up to 18 patients with severe or moderate forms of hemophilia A and B.
The main objective of the study is to assess the safety and tolerability of repeated subcutaneous administration of ALN-AT3 to patients with hemophilia. Secondary tasks include the assessment of clinical activity to reduce the levels of antithrombin circulating in the bloodstream and increase the production of thrombin against the background of the introduction of pharmacological dosages of the drug. The study will also evaluate the potential effect of ALN-AT3 on the frequency of bleeding. Preliminary results of this study indicate the possibility of correcting the phenotype associated with hemophilia by introducing ALN-AT3 and reducing the level of antithrombin in the blood.
Article by Alfica Sehgal et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia is published in the journal Nature Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru Based on Alnylam Pharmaceuticals: Alnylam and Collaborators Publish Pre-clinical Study Results in Nature Medicine on ALN-AT3, an Investigational RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders (RBD).
15.04.2015