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Ionis Touts Phase 3 Win, But Safety Worries Cloud Nerve Drug Study

Xconomy San Diego — 

Two RNA-based drugs for the same disease, a rare, crippling nerve condition called familial amyloid polyneuropathy (FAP) with no available treatments in the U.S., could soon be under an FDA review at the same time.

The first of those treatments, from Carlsbad, CA, Ionis Pharmaceuticals, is on its way there—but are the data are good enough to satisfy regulators and Ionis’s partner, GlaxoSmithKline?

It’s tough to say, because Ionis (NASDAQ: IONS) isn’t releasing many details yet, and some safety issues have emerged in clinical testing. Those concerns appeared to drive Ionis shares down in early trading, while rival Alnylam Pharmaceuticals (NASDAQ: ALNY) saw its shares shoot up (more below).

This morning Ionis said that its drug, inotersen, succeeded in a Phase 3, placebo-controlled study in 172 patients with FAP. Patients on the drug for 15 months had a statistically significant improvement, compared to placebo, on two tests that measure their symptoms: the “modified neuropathy impairment score,” or mNIS+7, a measure of symptoms like muscle weakness and reflexes; and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy, which evaluates how the disease is impacting patients’ lives.

Ionis, however, didn’t disclose the magnitude of the benefit on either test, or mention how the drug fared on secondary measures, like a change in body mass index—full details from the study will be presented at a future medical meeting.

What’s more, Ionis also said some “key safety findings” have caused it to change how it monitors patients. Three patients treated with inotersen had dangerously low platelet levels, or thrombocytopenia—two patients recovered, but the other died from a brain hemorrhage. A fourth patient whose platelet count dropped on inotersen stopped treatment. Four other inotersen patients also dropped out of testing due to kidney problems, some of which were severe.

The disclosures were particularly troubling given Ionis has seen thrombocytopenia in testing of some of its other RNA-based drugs. In a research note, Leerink Partners analyst Paul Matteis wrote the drug’s safety “remains a major question,” along with the possible “frequency/necessity of dose reductions.”

For its part, Ionis said it has since changed how it tests for low platelet counts and kidney problems and that all of the serious side effects occurred before these measures were implemented. Ionis said more than 80 percent of patients completed the Phase 3 trial, and over 95 percent of those patients are participating in an open-label extension study that will test the drug’s long-term impact.

On a conference call, Ionis senior vice president of drug discovery Brett Monia said the safety concerns can be monitored, are “manageable” and that “early signals [of safety problems] are reversible.” In a statement, he said the “preliminary results suggest a favorable benefit-risk profile” for inotersen. Will the FDA agree, given the lack of available alternatives? Ionis said preparations for approval applications are underway, and the coming decision of partner GSK could say a lot. The British pharma has the option to license inotersen before Ionis submits those applications, pending the review of more data. On the call, CEO Stanley Crooke said Ionis “assumes” GSK will exercise its option, but “will be delighted” to commercialize inotersen on its own if GSK passes.

FAP is a form of transthyretin amyloidosis, an inherited condition in which amyloid proteins build up in tissues of the body and cause damage to the nerves, heart, and other organs. About 10,000 people have the nerve-damaging form, FAP, and they tend to live another 5 to 15 years after symptoms crop up (another form, affecting the heart, is more prevalent).

The only treatment options for FAP patients are a liver transplant, or Pfizer’s tafamidis (Vyndaqel), which is approved in Europe but not in the U.S. Ionis is in a race with another maker of RNA-based drugs, Alnylam (NASDAQ: ALNY), to develop a new class of treatments for the disease. Results from a Phase 3 study of Alnylam’s rival patisiran are expected later this year. Matteis wrote that given the similarities between the two drugs, Ionis’s data “virtually de-risks patisiran, barring an unexpected safety concern.”

On the call, Monia made a case for inotersen’s superiority. Ionis’s drug is administered at home through a once-weekly subcutaneous injection. Patisiran is given intravenously at a doctor’s office once every three weeks, and patients have to be prepped with analgesics and steroids, long-term use of which, Monia said, might lead to other complications.

Investors, however, sent Ionis shares down more than 8 percent in pre-market trading Monday, while Alnylam shares surged more than 14 percent.