UniQure Unveils Expanded Gene Therapy Pipeline

Rare Daily Staff

UniQure today announced the expansion of its research pipeline with new AAV gene therapy approaches to treating hemophilia A, Fabry disease, and spinocerebellar ataxia type 3 at the company’s Research & Development Day in New York City.

The company said its new product candidate AMT-180 is a novel hemophilia A gene therapy that has the potential to treat all hemophilia A patients including those with past and current inhibitors. It is a one-time, intravenously-administered, AAV5-based gene therapy incorporating a proprietary modified factor IX gene, Super9, that has been demonstrated in preclinical studies to circumvent inhibitors to FVIII.

Hemophilia is a rare, genetic disorder in which the ability of a person’s blood to clot is impaired. People with hemophilia A experience bleeding episodes that can cause pain, irreversible joint damage and life-threatening hemorrhages due to a deficiency of the clotting protein factor VIII. About 30 percent of patients with severe hemophilia A will develop an inhibitor that neutralizes the infused factor VIII activity. This patient population has in the past been excluded from gene therapy approaches in clinical development.

The company said animal studies suggest that AMT-180 may lead to durable expression in hemophilia A patients and may provide long-term prevention of bleeds.

AMT-190, a second new product candidate, is a differentiated gene therapy for the treatment of Fabry disease. Fabry disease is an inherited lysosomal storage disorder. In patients living with Fabry disease, metabolic waste accumulates in various cells throughout the body causing progressive clinical signs and symptoms of the disease as a result of a deficiency of the GLA enzyme. Current treatment options, which consist of bi-weekly intravenous enzyme replacement therapy, have no therapeutic benefit in patients with advanced renal or cardiac disease. Studies have also shown that a majority of male patients develop antibodies that inhibit the GLA enzyme and interfere with the therapeutic efficacy of enzyme replacement therapy.

AMT-190 is a one-time, intravenously-administered, AAV5-based gene therapy designed to circumvent the antibodies that can inhibit efficacy in Fabry patients. AMT-190 incorporates a modified version of the enzyme these patients need that is structurally similar to the actual enzyme but is not recognized by the GLA-neutralizing antibodies. As such, the company believes AMT-190 has the potential to be a more effective, longer-term treatment of Fabry disease.

Preclinical studies showed a single dose of AMT-190 could potentially lead to long-term expression of GLA in the liver, kidneys, and heart, with no loss of expression due to inhibitors.

The final new gene therapy candidate UniQure unveiled during the event was AMT-150, a novel treatment for spinocerebellar ataxia type 3, a central nervous system disorder. Spinocerebellar ataxia type 3, also known as Machado-Joseph disease, is caused by a CAG-repeat expansion in the ATXN3 gene that results in an abnormal form of the protein ataxin-3. People with SCA3 experience brain degeneration that results in movement disorders, rigidity, muscular atrophy, and paralysis. There is currently no treatment available that slows the progressive course of this lethal disease.

AMT-150 is a one-time, intrathecally-administered, AAV gene therapy incorporating the company’s proprietary MiQure silencing technology that is designed to halt ataxia in early manifest SCA3 patients.

Preclinical studies show that a single administration of AMT-150 results in sustained expression and efficient processing with on-target engagement. They also show that AMT-150 appears to be safe due to the lack of off-target activity. The company is currently performing studies in large animals to demonstrate further safety and efficacy.

“The addition of these gene therapy candidates for indications in the liver and CNS brings us yet another step closer towards UniQure’s goal of delivering transformational medicine to patients suffering from genetic diseases,” said Sander van Deventer, chief scientific officer at UniQure.

November 19, 2019
Photo: Sander van Deventer, chief scientific officer at UniQure.