Isis Pharmaceuticals, Inc. and GlaxoSmithKline have agreed to amend the clinical development plan and financial terms relating to ISIS-TTRRx to reflect the accelerated development plan for the drug. ISIS-TTRRx is an antisense drug in development with GSK for the treatment of TTR amyloidosis, a severe and rare genetic disease characterized by progressive dysfunction of peripheral nerves and/or heart tissue.
The revised development plan anticipates initiation of a phase 2/3, registration-directed, clinical study later this year. ISIS-TTRRx is one of several promising drugs in Isis' pipeline that Isis expects will begin registration-directed studies within the next several years.
"In our phase 1 study, we demonstrated that ISIS-TTRRx was generally well tolerated and produced dose-dependent significant reductions in TTR protein with several subjects reaching TTR protein levels that were below the limit of assay detection," said Brett Monia, senior vice president, antisense drug discovery at Isis. "We anticipate initiating the next clinical study this year, which will evaluate the effects of ISIS-TTRRx on neurological dysfunction and on quality-of-life in patients with familial amyloid polyneuropathy."
Under the terms of the original collaboration agreement with GSK, which includes five programs in addition to the TTR programme, Isis is eligible to receive on average up to $20 million in milestone payments per program, before phase 2 proof-of-concept, plus a licensing fee, additional post-licensing milestone payments and double-digit royalties on sales from each product. Isis has already received $10 million in milestone payments from GSK related to the development of ISIS-TTRRx.
Under the amended terms of the agreement Isis will receive a $2.5 million upfront payment and is eligible to earn a $7.5 million milestone payment upon the initiation of the ISIS-TTRRx phase 2/3 study. Isis is also eligible to earn an additional $50 million in pre-licensing milestone payments to support the ISIS-TTRRx phase 2/3 study. In addition, GSK has increased the regulatory and sales milestones payable to Isis should the product achieve registration and meet certain sales thresholds. Isis will also receive double-digit royalties on sales of ISIS-TTRRx.
"We have a robust pipeline of novel new drugs. Many of which, including ISIS-TTRRx, could advance into registration studies in the next 12 to 18 months. Together with GSK, we have been able to rapidly advance the TTR programme from research to late-stage clinical development in just over two years," said B. Lynne Parshall, chief operating officer and chief financial officer at Isis. "Under the updated plan, Isis continues to manage the clinical development of ISIS-TTRRx while benefiting from GSK's late-stage development and commercial expertise. We believe that ISIS-TTRRx could be a best-in-class medicine for patients who have limited therapeutic options."
Transthyretin amyloidosis is a genetic disease in which the patient inherits a mutant gene that produces a misfolded form of transthyretin (TTR) protein, which progressively accumulates in tissues, impairing their function. In patients with transthyretin amyloidosis, both the mutant and normal forms of TTR can build up as fibrils in tissues, including heart, peripheral nerves, and the gastrointestinal tract. The presence of TTR aggregates interferes with the normal functions of these tissues, and as the TTR protein aggregates enlarge more tissue damage occurs and the disease worsens. There are two common types of transthyretin amyloidosis, familial amyloid polyneuropathy(FAP), which affects more than 10,000 patients worldwide, and familial amyloid cardiomyopathy (FAC), which affects more than 40,000 patients worldwide. Patients with FAP have TTR build up in peripheral nerve tissue leading to the loss of nerve function and wasting. Patients with FAC have TTR build up in the heart muscle and succumb to heart failure five to six years after symptom onset. ISIS-TTRRx is an investigational drug that is designed to inhibit the production of all forms of TTR, and could offer an alternative approach to treat all types of transthyretin-related amyloidosis.