Hemophilia A is caused by missing or defective factor VIII (FVIII), a clotting protein. About 30% of patients with severe hemophilia A develop inhibitors, or antibodies, that neutralize FVIII activity.
AMT-180 is designed for one-time intravenous (IV) delivery and uses a type of viral vector called adeno-associated virus 5 (AAV5). The potential therapy contains a modified factor IX gene known as Super9, which has shown an ability to bypass inhibitors to FVIII in preclinical studies, suggesting it may be beneficial for a patient population previously excluded from gene therapy approaches.
A proof-of-concept study in mice also demonstrated that Super9 had clinically relevant activity mimicking FVIII, and was not associated with exaggerated blood clotting.
In primates, a single AMT-180 dose led to expression levels corresponding to FVIII activity likely to be clinically relevant in hemophilia A patients with or without inhibitors, the company said. These findings were supported by Super9-induced activation of the blood clotting protein thrombin in FVIII-depleted human blood with or without inhibitors.
Results suggest long-term prevention of bleeds in hemophilia A patients treated with AMT-180, the company said.
uniQure also recently issued a company update on ongoing patient enrollment in its open-label Phase 3 trial (NCT03569891) of a potential gene therapy for hemophilia B, called AMT-061. More information on participation is available here.
And it announced that three patients taking part in a Phase 2b study (NCT03489291) of AMT-061, which is also still enrolling eligible patients, have already been treated. Information for this trial is available here.
At its Research & Development (R&D) Day, held on Nov. 19 in New York City, uniQure also announced the development of other one-time AAV approaches to possibly treat Fabry disease and spinocerebellar ataxia type 3 (SCA3).
For Fabry disease, uniQure is advancing AMT-190. This therapy is intended to evade anti-GLA protein antibodies found in most male patients, so as to be a more effective and longer-lasting therapy.
For SCA3, also known as Machado-Joseph disease, uniQure is developing AMT-150, which uses the company’s new miQURE technology to halt ataxia — a lack of voluntary coordination of muscle movements — in patients with early disease symptoms.
“We are very proud of the progress the Company has made to deliver extensive preclinical data for these new gene therapy programs that expand our pipeline and further validate uniQure’s potential best-in-class vector delivery platform,” Sander van Deventer, MD, PhD, uniQure’s chief scientific officer, said in a press release.
The new gene therapy candidates represent a step forward “towards uniQure’s goal of delivering transformational medicine to patients suffering from genetic diseases. We look forward to advancing these programs closer to the clinic in 2019,” van Deventer added.
uniQure also presented advancements in technology and manufacturing, topped by miQURE, a technology platform designed to safely degrade disease-causing genes. miQURE is intended to induce long-lasting gene silencing of the entire target organ. Improved tissue specificity and more pronounced gene expression lowering were seen in preclinical studies. Besides AMT-150, miQURE has been incorporated into AMT-130, a Huntington’s disease treatment candidate.
The company also showed data on a novel promoter — the DNA portion that initiates gene expression — for liver-directed gene therapies, indicating up to 40-fold greater protein expression compared to the referenced alternative. This promoter will be incorporated in AMT-180.
A replay of the R&D Day webcast and a copy of the presentation are available here.