Date: 2017-12-09
Type of
information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting9
Company: Uniqure (The Netherlands)
Product: AMT-061
Action
mechanism:
- gene therapy. AMT-061 and AMT-060, the latter of which has been tested in 10 patients in an ongoing Phase I/II clinical trial, are identical in structure apart from two nucleotide substitutions in the coding sequence for FIX. The gene variant, referred to as FIX-Padua, expresses a protein with a single amino acid substitution that has been
reported in multiple preclinical and nonclinical studies to provide an approximate 8 to 9-fold increase in FIX
activity compared to the wild-type FIX protein. All other critical quality attributes of AMT-061 are expected to
be comparable to those of AMT-060, as AMT-061 utilizes the same AAV5 capsid and proprietary insect cell-based
manufacturing platform.
- The FDA has agreed that AMT-061 will be included under the existing Breakthrough Therapy designation and Investigational New Drug (IND) for AMT-060. The EMA also has agreed that AMT- 061 will be included under the current PRIME designation.
- In October 2017, uniQure has acquired a patent family, with claims issued in the U.S., that broadly covers a hyperactive variant of Factor IX carrying an R338L mutation (often referred to as "FIX-Padua") and its use in gene therapy for the treatment of coagulopathies, including hemophilia B. This patent family was acquired from the inventor, Professor Paolo Simioni, a renowned hemophilia expert at the University of Padua, Italy, who is widely recognized as the first to identify this mutant. Professor Simioni filed a PCT application on September 15, 2009, and patent applications are pending in the U.S., Europe, and Canada. The U.S. Patent and Trademark Office issued U.S. Patent 9,249,405 on February 2, 2016, which includes claims directed to Factor IX protein with a leucine at the R338 position of the protein sequence, nucleic acid sequences coding for this protein, and therapeutic applications, including gene therapy. Additional fast track divisional patent applications have also been filed in the U.S. and in Europe that would further strengthen uniQure's intellectual property position.
Disease: severe and moderately severe hemophilia B
Therapeutic
area: Rare diseases - Genetic diseases - Hematological diseases
Country:
Trial
details:
Latest
news:
- • On December 9, 2017, uniQure announced new nonclinical data on AMT-061, its investigational gene therapy
for patients with hemophilia B. The data have been presented in a poster session at the 59th American Society of Hematology (ASH) Annual. The data presented from the study in non-human primates demonstrated dose-dependent expression of human Factor IX protein (hFIX) and FIX clotting activity. Animals receiving the same dose of AMT-060 and AMT-061 showed comparable levels of hFIX protein, but the animals receiving AMT-061 demonstrated approximately 6.5-fold higher FIX activity compared to those receiving AMT-060. The goal of this non-human primate study was to evaluate the efficacy and safety of introducing the FIXPadua
variant into the AMT-060 cassette. The study also compared AMT-061 to AMT-060 with respect to liver transduction, circulating FIX protein levels, circulating FIX activity levels and toxicity.
- Cynomolgus monkeys in 6 groups (n = 3 per group) received a one-time intravenous administration of either AMT-060 (5x1012gc/kg), AMT-061 in a range of four doses (5x1011 to 9x1013gc/kg) or the vehicle control.
- Animals receiving AMT-061 showed clear, dose-dependent increases in FIX protein and an approximately 6.5-fold increase in FIX clotting activity compared to AMT-060.
• At a dose of 5x1012 gc/kg, AMT-061 FIX activity was at average of 58.9% of normal in week 4 to week 13 post administration, whereas AMT-060 FIX activity was 9.1% of normal during this same time period. AMT-060 and AMT-061 showed similar circulating vector DNA plasma levels, liver
distribution, liver cell transduction and transgene expression.
• Safety measures, including various markers of coagulation and fibrinolytic activation did not significantly differ between the groups, suggesting that there is no increased risk of thrombosis in animals expressing the Padua-FIX variant.
• No toxicological findings or target organ defects were detected after either AMT-060 or AMT-061 administration.
Uniqure is now looking forward to advancing this gene therapy candidate into a pivotal study in 2018.
- • On October 19, 2017, uniQure announced that following multi-disciplinary meetings with the FDA and the EMA, the company plans to expeditiously advance AMT-061, which combines an AAV5 vector with the FIX-Padua mutant, into a pivotal study in 2018 for patients with severe and moderately severe hemophilia B. The company has begun GMP production of AMT-061 in its Lexington facility and preparations for the pivotal study are underway.
- The study is expected to be an open-label, single-dose, multi-center, multi-national trial investigating the efficacy and safety of AMT-061 administered to adult patients with severe or moderately severe hemophilia B. The primary objective of the trial is to evaluate AMT-061 for prevention of bleedings. Secondary objectives include additional efficacy and safety aspects. Patients will serve as their own control, with a baseline established during a six-month observational lead-in
phase prior to treatment with AMT-061.
• Concurrent with the start of the six-month lead-in phase of the pivotal study, a short dose-confirmation study is expected to begin in the third quarter of 2018. Three patients will receive a single intravenous dose of AMT-061 at 2x1013 gc/kg and will be evaluated for a period of approximately six weeks
to assess FIX activity levels and confirm the dose. Each patient will continue to be followed longer term, and no lead-in phase is required for the dose confirmation study.
Is
general: Yes
