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uniQure Announces New Preclinical Data in Hemophilia A and Fabry Disease in Oral Presentations at the 22nd ASGCT Annual Meeting

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LEXINGTON, Mass. and AMSTERDAM, the Netherlands, May 02, 2019 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, will present today new preclinical data on its gene therapy candidates AMT-180 for the treatment of hemophilia A and AMT-190 for the treatment of Fabry disease. These data will be featured today in back-to-back oral presentations at the 22nd American Society for Gene and Cell Therapy (ASGCT) Annual Meeting in Washington D.C.

AMT-180 for Hemophilia A

Hemophilia A is an X-linked bleeding disorder resulting from a deficiency in coagulation Factor VIII that serves as a cofactor for Factor IX in the activation of the coagulation cascade. About 30 percent of the hemophilia A patient population develops inhibitors to Factor VIII over the course of the disease.
AMT-180 comprises a recombinant AAV5 vector incorporating a proprietary modified Factor IX hat, when activated through normal mechanisms, induces thrombin generation independently of Factor VIII.
Data from multiple in vitro and in vivo studies show that a single intravenous administration of AMT-180 results in dose-dependent, therapeutically meaningful Factor VIII-independent activity as measured by thrombin generation and one-stage clotting assay. AMT-180 is a differentiated approach that is suggested to be hepatocyte-friendly and non-thrombogenic based on the studies conducted to date and is expected to reduce and potentially prevent bleedings in hemophilia A patients with and without inhibitors.

AMT-180 Preclinical Data Findings
Proof-of-concept for AMT-180 was established through studies across two different animal models. The oral presentation at ASGCT features the following data:

  • Preclinical studies in FVIII-depleted human plasma show that AMT-180 induced clinically relevant thrombin activation, and up to 29% of Factor VIII-independent activity, in plasma with and without inhibitors.
  • The mechanistic proof-of-concept of AMT-180 was demonstrated in a hemophilia A mouse model, where a single intravenous administration of AMT-180 resulted in sustained, dose-dependent hemostatic effect as measured by one-stage clotting assay.
  • The studies further demonstrate that AMT-180 shows activation kinetics similar to native FIX and is not hyperactive.
  • A pilot study in non-human primates demonstrated that a single administration of AMT-180 resulted in sufficient FIX protein expression that translates to clinically relevant Factor VIII-independent activity in humans. No elevation of coagulation activation markers or signs of thrombi formation were observed.

“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.” stated Sander van Deventer, M.D., Ph.D., chief scientific officer at uniQure. “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.”

AMT-190 for Fabry Disease

Fabry disease is an X-linked genetic disorder resulting from a deficiency of α-galactosidase A (α-gal or GLA). The current standard of care for Fabry disease is bi-weekly infusions of enzyme replacement therapy, a treatment that has shown not to be effective in many patients due to poor targeting of target organs such as the kidney and heart. In addition, a significant number of patients develop antibodies to the enzyme, α-gal or GLA.
AMT-190 is a novel AAV5 gene therapy approach for Fabry disease that comprises a recombinant AAV5 vector incorporating a proprietary, exclusively licensed, modified NAGA (ModNAGA) variant. AMT-190 provides expression of ModNAGA, which shows a high structural resemblance to α-gal. This approach may have several advantages over α-gal therapies, including higher stability in blood, better biodistribution in the target organs, secondary toxic metabolite reduction and improved cross-correction of neighboring cells. ModNAGA is also effective in the presence of α-gal antibodies.
Data from in vitro and in vivo studies show that AMT-190 has the potential to become a one-time treatment option that improves upon the enzyme replacement standard of care with more efficient uptake in the kidney and heart and an improved immunogenicity profile.

AMT-190 Preclinical Data Findings

Proof-of-concept for AMT-190 was established through multiple studies in wild-type and Fabry mice. The oral presentation at ASGCT features the following data:

  • Preclinical in vitro studies demonstrated that the expression of ModNAGA results in GLA activity in cells and suggest that uptake of ModNAGA is mediated by the Mannose-6-phosephase (M6P) receptor.
  • In vivo studies in wild-type mice show that a single intravenous administration of AMT-190 resulted in a ten- to twenty-fold higher GLA activity in the plasma compared to the control group, suggesting that AMT-190 has the potential to provide therapeutically relevant GLA activity in plasma and in target organs.
  • These results were underscored by a study in GLA knock-out mice, demonstrating significantly increased GLA activity in plasma and significantly reduced Lyso-Gb3 in the target organs after a single dose of AMT-190. In silico and in vitro studies also show that the modifications introduced into NAGA pose a very low immunogenicity risk.

“These data show that AMT-190 has the potential to be a differentiated, one-time treatment option that could be used by all Fabry patients,” added Dr. van Deventer. “We will continue to advance our preclinical research toward our goal of developing a best-in-class gene therapy for Fabry disease.”
An overview of the AMT-180 and AMT-190 preclinical data presented at ASGCT can be found on the Investor section of uniQure’s corporate website.
About uniQure
uniQure is delivering on the promise of gene therapy – single treatments with potentially curative results. We are leveraging our modular and validated technology platform to rapidly advance a pipeline of proprietary and partnered gene therapies to treat patients with hemophilia, Huntington’s disease and other severe genetic diseases. www.uniQure.com