Safety Concerns Raised as Ionis Pharma's Inotersen Meets Both Primary Endpoints in Late-Stage Study

May 15, 2017
By Alex Keown, BioSpace.com Breaking News Staff

CARLSBAD, Calif. –Ionis Pharmaceuticals said its Phase III study of inotersen to treat patients with familial amyloid polyneuropathy (FAP) met primary and secondary endpoints. However, share prices are down more than 9 percent this morning following safety concerns raised in the trial.

Over a 15-month trial, Ionis said patients achieved statistically significant benefits compared to placebo in both the modified Neuropathy Impairment Score +7 and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy. Statistically significant differences were also observed for both endpoints at eight months.

However, Ionis also said treatment-emergent adverse events considered related to treatment were seen more commonly with inotersen than placebo. Over the course of the study, Ionis said three serious adverse events of thrombocytopenia were observed in inotersen-treated patients. One of those patients died due to intracranial hemorrhage. Additionally, Ionis said one inotersen-treated patient discontinued treatment due to non-serious thrombocytopenia. There were other problems as well that caused some of the patients to discontinue treatment. Four inotersen-treated patients discontinued treatment due to a renal observation; two patients met a predefined renal stopping rule and two experienced serious renal adverse events, one of whom experienced chronic renal insufficiency. One placebo-treated patient also met a predefined renal stopping rule, Ionis said.

Ionis said all five serious adverse events occurred before enhanced monitoring was fully implemented. A detailed review of safety data from the study is ongoing, the company said. More than 80 percent of the patients completed the study. Of those, more than 95 percent participated in the open-label extension study.

In its statement this morning, Ionis provided extensive detail of the safety issues concerning inotersen, however the company did not provide much in the way of efficacy data. In a statement, Brett P. Monia, senior vice president of drug discovery and franchise leader for oncology and rare diseases at Ionis, only said researchers “observed a benefit in disease progression in patients treated with inotersen, regardless of disease stage (Stage 1 and Stage 2) or TTR mutation…”

“We believe these preliminary results suggest a favorable benefit-risk profile for inotersen in patients with FAP,” Monia added.

While shares of Ionis have plunged, rival drugmaker Alnylam has seen a spike in its share price this morning. Alnylam stock is up nearly 19 percent as investors may be looking at its lead drug patisaran as a safer alternative to Ionis’ inotersen to treat FAP, one of the three forms of TTR amyloidosis.

TTR amyloidosis is a severe, progressive and fatal disease with multiple overlapping clinical manifestations. There are three forms of TTR amyloidosis: familial amyloid polyneuropathy, FAP, familial amyloid cardiomyopathy, FAC, and wild type (wt)-TTR amyloidosis. The disease is caused by the accumulation of misfolded TTR protein in a broad range of tissues and organs, including peripheral nerves, heart, intestinal tract, eyes, kidneys, central nervous system, thyroid and bone. The accumulation of TTR amyloid deposits leads to organ failure and eventually death.

Initially, Ionis was collaborating with GlaxoSmithKline on the development of inotersen. Nearly one year ago though, GSK backed off development following the trial being placed on clinical hold due to safety concerns. GSK maintains the option to license inotersen following review of additional data and prior to the submission of regulatory applications, Ionis said. The company is preparing to seek regulatory approval of inotersen.