A single dose of the experimental gene therapy AMT-180 promotes clinically meaningful blood-clotting activity, independent of factor VIII levels, in mouse and primate models of hemophilia A, a study shows.
These preclinical findings were discussed in a presentation, “Towards AAV5-Mediated Gene Therapy for Hemophilia A with a Factor IX Variant that Functions Independently of FVIII” (abstract #959), during the 22nd American Society for Gene and Cell Therapy annual meeting recently held in Washington, D.C.
Hemophilia is a genetic disorder that affects blood clotting, leading to excessive bleeding. In hemophilia A, this blood-clotting defect is caused by the lack of a specific clotting protein called factor VIII (FVIII), which normally works together with factor IX (FIX) to activate the blood coagulation process.
Patients with hemophilia A are usually treated with intravenous infusions of man-made versions of FVIII. However, about 30% of them start producing inhibitors against these infused FVIII proteins at some point during the course of the disease, rendering the treatment ineffective.
AMT-180 is being developed by uniQure as a gene therapy candidate for the treatment of hemophilia A patients with or without FVIII inhibitors. It works by using a special viral vector to safely deliver a proprietary modified version of the FIX gene, called Super9. When active, this enhanced version of FIX is believed to trigger blood coagulation (thrombin activation) independent of FVIII levels.
Preclinical studies revealed that treatment with AMT-180 could improve blood coagulation by up to 29% in FVIII-independent blood-clotting activity in human plasma samples depleted of FVIII, regardless of the presence of FVIII inhibitors. In addition, the activity of AMT-180 was found to be similar to that of the naturally produced human FIX clotting protein.
Researchers tested the safety and efficacy of AMT-180 in mouse models of the disease as well as in non-human primate models of hemophilia A.
A single intravenous administration of AMT-180 was found to effectively trigger a sustained hemostatic response (a process that stops bleeding) in mice with hemophilia A. Similarly, a single dose of the investigational gene therapy induced the production of functional FIX protein in non-human primates, in levels believed to be sufficient to trigger blood coagulation independent of FVIII in human patients.
“Therapy development based on a FIX variant is feasible and indicate that therapeutic relevant FVIII mimetic activity could be achieved in hemophilia A patients using this approach,” the researchers wrote.
In general, treatment with AMT-180 was well-tolerated in both animal models, and was not associated with higher risks of thrombogenicity (formation of blood clots that may block blood circulation).
“Data from these preclinical studies show the exciting potential of AMT-180 to provide clinically meaningful Factor VIII-independent activity after a one-time administration,” Sander van Deventer, MD, PhD, chief scientific officer at uniQure, said in a press release.
“We are particularly encouraged by the broad potential of AMT-180 in treating both patients with and without inhibitors, and the unique approach of AMT-180 that potentially circumvents durability issues because of its hepatocyte-friendly profile,” he added.
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