Gene therapies are being develop to treat diseases caused by genetic mutations. It involves replacing the faulty gene in patients with a healthy gene. AMT-061 is a treatment that uses a viral vector that contains the gene for a mutated factor IX (FIX) called the Padua variant (FIX-Padua). FIX is an important clotting protein that is deficient in patients with hemophilia B.
In the Padua variant, the gene mutation leads to a higher amount of the protein. In fact, FIX-Padua leads approximately an eight to nine-fold increase in FIX activity compared to normal FIX protein. This substantial increase in FIX activity can significantly help patients with hemophilia B.
“I believe AMT-061 has the potential to be an important gene therapy for patients suffering with hemophilia B,” Dr. Steven Pipe, MD, professor of pediatrics and pathology and pediatric medical director of the hemophilia and coagulation disorders program at the University of Michigan, said in a press release.
“Based on the data generated to date, AMT-061 may be the first gene therapy to provide durable, curative benefits to nearly all patients with hemophilia B, without the complications associated with capsid-related immune responses. I very much look forward to serving as an investigator in this exciting Phase 3 program,” he said.
The U.S. Food and Drug Administration granted Breakthrough Therapy designation to AMT-061, and has approved uniQure’s Investigational New Drug application.
uniQure has also reached an agreement with the FDA and the European Medicines Agency on the proposed clinical trial for AMT-061, which will be tested in adult patients with severe or moderately severe hemophilia B. A dose-confirmation study will start the 2018 study, which is expected to begin in the summer. After receiving a dose of AMT-061, patients will be assessed for six weeks to determine FIX activity levels.
To determine the tolerability and safety of AMT-061, a preclinical study of AMT-061 in non-human primates at four different doses was conducted. Results showed there was a strong correlation between the dosage of AMT-061 and the levels of FIX.
uniQure was able to determine, based on this study, that AMT-061 should be administered at a dose of 2 x 1013 gc/kg, which could lead to the production of 30% to 50% of normal FIX levels.
Data from this preclinical study demonstrated that the gene therapy was well-tolerated with no significant toxicological findings.
AAV5-based gene therapies are found to be safe and well tolerated across multiple clinical trials. In fact, no patients treated with this therapy in any of uniQure’s clinical trials have experienced immune reaction to AAV5, indicating that most hemophilia B patients may be eligible for treatment with AMT-061.
“Our mission in hemophilia B has always been to develop the safest and most effective gene therapy with the broadest application to patients. We believe AMT-061 moves us closer to this goal, as it has the potential to provide optimized clinical and tolerability benefits to nearly all severe and moderately severe patients with hemophilia B,” said Matthew Kapusta, CEO of uniQure.
The manufacturing for the gene therapy candidate has begun, with material being produced at commercial scale for the 2018 clinical trial.
“We are delighted to have received constructive guidance from both the FDA and EMA, which we believe allows us to expeditiously advance AMT-061 into a pivotal study next year, as previously planned. In anticipation of this, we have begun GMP production of AMT-061 in our Lexington facility and preparations for the pivotal study are underway,” Kapusta said.
In another press release, uniQure announced it has acquired a patent family for the FIX-Padua variant and its use in gene therapy for diseases such as hemophilia B. This patent has been issued in the U.S., while patents are currently pending in Europe and Canada.