Rare Disease Report

Ionis Filing NDA Next Week for ATTR Amyloidosis Drug Based on Positive Phase 3 Data

NOVEMBER 02, 2017
James Radke
Today, Ionis Pharmaceuticals announced new data from their phase 3 study testing inotersen in patients with hereditary ATTR amyloidosis was presented at the ATTR Amyloidosis Meeting in Paris, France.

And the results are very impressive. The 2 primary endpoints — Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and modified Neuropathy Impairment Score +7 (mNIS+7) — strongly favored inotersen over placebo in the 15-month study.

ATTR amyloidosis is a progressive genetic disease due to misfolded transthyretin (TTR) proteins that leads to the deposition of amyloid fibrils in different organs.

In ATTR amyloidosis with polyneuropathy, the amyloid deposits mostly affect the peripheral or autonomic nerves. Common symptoms with ATTR amyloidosis with peripheral neuropathy may include numbness, tingling, pain, weakness, and loss of sensations. Common symptoms with ATTR amyloidosis with autonomic neuropathy may include postural hypotension, urinary retention, impotence, body temperature irregularities, and gastrointestinal problems.

The disease is a progressive one and if left untreated, most will die within 3 – 15 years of symptom onset. There are currently no treatment options for these patients, other than a possible liver transplant, but there are 2 orphan drugs in late stage development for treating ATTR amyloidosis—Ionis’ inotersen and Alnylam’s patisiran.  Inotersen is an antisense medication and patisiran is a RNA interference drug. Both are designed to reduce the production of TTR.

Last month, Alnylam reported statistically significant results with patisiran and the company stated they plan to submit a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) in late 2017. Today, Ionis responded with their own statistically significant data and stated they intend to file a NDA with the FDA next week, according to the webcast they hosted early this morning.

The NEURO-TTR study presented at the ATTR Amyloidosis Meeting is a randomized, placebo-controlled phase 3 study involving 172 patients with ATTR amyloidosis with polyneuropathy.

After 15 months of weekly subcutaneous injections, the two co-primary endpoints, Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and modified Neuropathy Impairment Score +7 (mNIS+7) showed the statistically significant superiority of inotersen over placebo.

Figure 1. Quality of Life Scores after 8 Months

Figure 2. Quality of Life Scores after 15 Months

Figure 3. Neuropathy Scores after 8 Months

Figure 4. Neuropathy Scores after 15 Months

Three patients taking inotersen developed thrombocytopenia during the study. Two patients recovered and 1 patient died due to an intracranial hemorrhage. A 4th patient with non-serious thrombocytopenia discontinued treatment.

In addition, 6 patients taking inotersen experienced serious renal adverse events and 2 of those patients discontinued treatment. Enhanced platelet and renal monitoring was implemented during the study to support early detection and management of these issues.

Most common adverse events included thrombocytopenia/platelet count decreases, nausea, pyrexia, chills, vomiting and anemia.

In a news release, Brett P. Monia, senior vice president of drug discovery at Ionis Pharmaceuticals said, "The results from the NEURO-TTR study support a favorable benefit-risk profile for inotersen in patients with hATTR. We believe inotersen has the potential to give people living with this devastating, progressive, fatal disease new hope and the ability to regain freedom from the burden of their disease."

Monia added that the company plans to file for marketing authorization in the EU tomorrow (Friday, November 3, 2017) and file a NDA with the FDA next week.

Images obtained from Ionis Pharmaceuticals’ webcast.

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