Isis Pharmaceuticals announced positive data from an ongoing open-label extension (OLE) study of ISIS-TTRRx in patients with familial amyloid polyneuropathy (FAP).  

FAP patients completing the ongoing phase 3 study are eligible to enroll in this OLE study in which all patients receive ISIS-TTRRx. An analysis conducted on the first group of patients to reach three months of treatment in the OLE study showed a reduction in transthyretin (TTR) protein levels up to 92 per cent with a median reduction of 78 per cent compared to patients' baseline TTR levels at entry into the phase 3 study. Patients continue to be enrolled as they complete dosing in the phase 3 study.

"TTR amyloidosis is a devastating progressive and fatal disease.  FAP is a genetic disease in which mutations in the TTR gene cause the TTR protein to accumulate as amyloid in tissues, peripheral nerves and major organs and impair their function. The substantial reduction in TTR protein observed in this study suggests that ISIS-TTRRx could potentially be an important new treatment option for patients with TTR amyloidosis who have very limited therapeutic options," said Merrill D. Benson, M.D., professor of medical genetics at Indiana University.

"We are encouraged by the high rate of patient retention observed in our phase 3 registration study and by the high rate of enrollment in the OLE study.  We believe that the convenience of a once weekly, at home subcutaneous injection of ISIS-TTRRx is a significant contributing factor for the high retention rate of our phase 3 study and for the robust enrollment of our OLE study. In addition, a blinded safety analysis of the ongoing phase 3 study shows the safety and tolerability profile we have observed to date with ISIS-TTRRx supports continued development. Notably, the injection site reactions were predominantly mild and infrequent, occurring in only about 1per cent of all injections," said Brett Monia, senior vice president of drug discovery at Isis Pharmaceuticals.

"The substantial reduction in TTR protein together with our safety profile and our high patient retention rate gives us confidence that ISIS-TTRRx may have a significant impact on the treatment of this disease."

In a platform presentation titled, 'A phase 3 Study to Evaluate ISIS-TTRRx in Patients with Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP): Study Design and Baseline Demographics', Dr. Benson reported that in the first thirteen patients to enter the OLE study, reductions of up to 92 per cent in TTR protein after thirteen weeks of treatment with ISIS-TTRRx were observed.  Across all patients enrolled in the phase 3 study, 27 TTR mutations were represented to date, including the Val30Met mutation, which is the most common mutation found in patients with FAP. ISIS-TTRRx is designed to reduce all forms of TTR, including both mutant and wild type, and therefore should provide therapeutic benefit to any FAP patient regardless of that patient's individual TTR mutation.

ISIS-TTRRx was also highlighted in a second platform presentation titled, 'Development of ISIS-TTRRx for Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP)'. In this presentation, Dr. Fred Derosier, executive director of clinical development at Isis Pharmaceuticals, provided an overview of the ISIS-TTRRx programme including the phase 1 study, in which ISIS-TTRRx achieved reductions of up to 96 percent in TTR protein levels.

 The ongoing phase 3 study is designed to assess the effects of ISIS-TTRRx on neurological dysfunction and on quality of life in patients with FAP.  Data from this study is planned for the first half of 2017.

The open-label extension study of ISIS-TTRRx in patients with FAP who have completed all fifteen months of dosing in the Phase 3 study.

An investigator-initiated open-label study being conducted by Dr. Merrill Benson in patients with familial cardiomyopathy (FAC) and senile systemic amyloidosis (SSA). This ongoing study is designed to assess the safety, tolerability and efficacy of ISIS-TTRRx in these patients.

A phase 3 study in patients with TTR-related cardiomyopathy that GSK anticipates initiating later this year. A phase 3 study in Japan in patients with FAP that GSK anticipates initiating later this year.

ISIS-TTRRx is a gen 2.0+ antisense drug Isis is developing with GSK for the treatment of TTR amyloidosis. ISIS-TTRRx is administered as a once weekly subcutaneous injection and is designed to inhibit the production of all forms of TTR protein, including both mutant and wild type, offering a unique approach to treat all types of TTR amyloidosis.

The phase 3 study of ISIS-TTRRx is a randomised, double-blind, placebo-controlled, international study designed to support an application for marketing approval of ISIS-TTRRx in patients with FAP. The fifteen month study will measure the effects of ISIS-TTRRx on neurological dysfunction and on quality-of-life.

TTR amyloidosis is a severe, genetic and fatal disease in which patients with TTR amyloidosis experience TTR build up in major organs, including peripheral nerves, heart, intestinal tract, kidney and bladder. Patients with FAP experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking.

These patients also accumulate TTR in major organs, which progressively impacts their function and eventually leads to death. Therapeutic options for the treatment of FAP are very limited and there are currently no drugs approved for the treatment of FAP in the United States.