Isis Pharmaceuticals, Inc. announced that it has designated the second development candidate, ISIS-AATRx, in its collaboration with GlaxoSmithKline (GSK). Isis earned a $5 million milestone payment from GSK for the selection of ISIS-AATRx. ISIS-AATRx is an anti-sense drug designed to treat liver disease caused by alpha-1 antitrypsin deficiency, or AATD, by inhibiting the production of an abnormal protein, which accumulates and causes damage in the liver. AATD-associated liver disease is a rare disease that can lead to severe and sometimes fatal liver dysfunction. Isis will develop ISIS-AAT Rx to phase II proof-of-concept, at which time GSK has the option to license the drug.

“Our collaboration with GSK is off to a very successful start. Within less than 2 years we have identified two development candidates, with the first, ISIS-TTRRx, expected to finish our phase I study this year and poised to start phase II next year. This collaboration exemplifies our ability to quickly select targets and discover drugs with promise to treat severe and rare diseases,” said Brett P Monia, vice president of Drug Discovery and Corporate Development. “We are pleased to continue to benefit from GSK's expertise as we further expand the breadth of our severe and rare disease franchise and broaden our focus on additional life-threatening diseases for patients who have very limited treatment options.”

ISIS-AATRx is an anti-sense drug designed to inhibit the production of alpha-1 anti-trypsin, or AAT, for the treatment of liver disease in patients with AATD. AATD is a genetic disease that affects 1 out of every 2,500 people in the United States and can lead to severe liver disease, including liver scarring, cirrhosis, and liver cancer. There are currently no available therapies for patients with AATD-associated liver disease, and liver transplantation is the only available option for patients who develop severe liver dysfunction. Symptoms of AATD-associated liver disease can manifest as early as infancy, and it is the most common genetic disease for which paediatric liver transplantation is performed. It is estimated that 10-15 per cent of all liver transplant candidates have AATD.

“AATD is an under-diagnosed disease that affects the lungs and, in some patients, can also lead to severe liver damage, end-stage liver disease and liver cancer. Unfortunately, patients with AATD-associated liver disease currently have no therapeutic options and are only treated to alleviate the symptoms associated with liver damage and scarring. In cases of severe liver damage, liver transplantation is the only option,” said Jeff Teckman, MD, Professor of Paediatrics and Biochemistry and director of Paediatric Gastroenterology and Hepatology at Saint Louis University. “We are encouraged by this therapeutic approach, which could, for the first time, offer an effective and selective treatment for patients with liver disease due to AATD.”

In 2010, Isis entered into a strategic alliance with GSK to develop RNA therapeutics for rare and infectious diseases. With the selection of ISIS-AATRx, Isis has earned $53 million in upfront fees and milestone payments and is eligible to receive license fees and milestone payments, totalling nearly $1.5 billion, in the event all six programmes are successfully developed for one or more indications and commercialized through to pre-agreed sales targets.

AATD is a genetic disorder in which the patient does not produce normal AAT, a protein primarily produced in the liver that protects lung tissue from damage. Patients with AATD inherit a mutant gene from one or both parents to produce misfolded AAT protein, which can progressively accumulate in the liver and cause liver disease. Patients who inherit a mutant gene from both parents are characterized as severe AATD and are at increased risk for developing serious lung conditions, including emphysema, chronic obstructive pulmonary disease (COPD), asthma and chronic bronchitis. Furthermore, approximately 10 per cent of infants and 15 per cent of adults with severe AATD experience liver damage. ISIS-AAT Rx is designed to inhibit the production of abnormal AAT in patients with AATD and prevent accumulation of misfolded AAT in the liver, offering a potentially unique approach to treat AATD-associated liver disease.

Isis is exploiting its leadership position in anti-sense technology to discover and develop novel drugs for its product pipeline and for its partners.