Clinical Data Phase 2 Investigator-initiated (Benson) Open-label Study Results
"Data from multiple endpoints support cardiomyopathy disease stabilization in patients treated with IONIS-TTRRx.  The MRI data demonstrated disease stabilization, as measured by left ventricular mass, as compared to both baseline values and from our published1natural history data. The observation of disease stabilization in patients treated for 12 months with IONIS-TTRRx, differs from what we observed in our recent natural history study, which used the same MRI measurements to follow disease progression over a year," saidMerrill D. Benson, M.D., professor of pathology and lab medicine, medical and molecular genetics at Indiana University School of Medicine. "Last year, we reported similar data on the first three patients in the study to achieve 12 months of dosing with IONIS-TTRRx. These new data, which now include a total of eight patients out of 22 enrolled who have now been treated with IONIS-TTRRx for 12 months, support and extend our previous observations."

• Patients entering the Phase 2 IONIS-TTRRx study had baseline interventricular septum thickness (IVS) ≥1.3cm. In this study, patients receive one injection of IONIS-TTRRxonce a week.
• The first eight patients treated with IONIS-TTRRx had a meandecrease of 4 percent in left ventricular mass from baseline as measured by MRI at 12 months.  This compares favorably to Dr. Benson's published natural history study in similar patients with an IVS ≥1.3cm at study entry who had a meanincrease of 14 percent in left ventricular mass as measured by MRI at 12 months.
• Patients in the Phase 2 IONIS-TTRRx study also demonstrated evidence for disease stabilization in multiple additional endpoints at 12 months, including, IVS thickness, global strain, the cardiac biomarker B-type natriuretic peptide (BNP) and the functional endpoint, 6-minute walk test (6MWT).
• Safety and tolerability data were presented on all of patients treated with IONIS-TTRRx in the Phase 2 IONIS-TTRRx study (n=22). No drug related serious adverse events have been reported. Three patients developed the need for cardiac pacing.  Moderate decreases in platelets were observed in some patients, but no serious platelet declines have been observed to date in this study. Injection site reactions were predominantly mild and infrequent, occurring in less than 2% of all injections. Transient pruritus was observed in two patients. Two patients reported fatigue lasting two to four days after dosing.
• The study is progressing and was recently amended to extend treatment from 24 to 36 months.

Phase 3 NEURO-TTR Open-label Extension (OLE) Study Results
New data from the ongoing open-label extension (OLE) study of IONIS-TTRRx in patients with familial amyloid polyneuropathy (FAP) who have completed the Phase 3 NEURO-TTR study was also presented at the ISA meeting. An analysis conducted on patients with 12 different mutations who reached up to 12 months of treatment in the NEURO-TTR OLE study showed approximately equal reduction of both wild-type and mutant TTR levels as measured by liquid chromatography-mass spectrometry (LC-MS). Patients continue to be enrolled in the OLE as they complete the Phase 3 NEURO-TTR study.  The Phase 3 NEURO-TTR study is expected to complete in the first half of 2017."TTR amyloidosis is a progressive, debilitating, fatal disease with multi-organ failure and limited treatment options. TTR amyloidosis patients who have the cardiomyopathy form of the disease progress rapidly and typically die within three to five years. We are pleased by the positive data from Dr. Benson's ongoing investigator initiated study in patients with TTR amyloid cardiomyopathy. We are also encouraged by the substantial reductions in TTR protein we have observed in patients, which appears to be independent of the presence or nature of the mutation in the TTR gene," said Brett Monia, senior vice president of drug discovery and franchise leader for oncology and rare diseases at Ionis Pharmaceuticals.  "We believe that the product profile including the convenience of dosing for IONIS-TTRRx as one subcutaneous injection, once a week with no premedication requirements contributes significantly to the high rate of patient retention in our Phase 3 NEURO-TTR study and the high rate of eligible patients enrolling in the OLE study. Given the potential risk/benefit profile, we believe IONIS-TTRRx will be the preferred treatment option for patients with TTR amyloidosis."