Ionis says it gathered promising PhIII data for a top rare disease drug, but serious safety questions remain

Ionis Pharmaceuticals $IONS says that its Phase III study of inotersen (IONIS-TTRRx) hit both primary endpoints in patients with rare cases of familial amyloid polyneuropathy (FAP). But investigators also spelled out just how dangerous this drug can be, clouding its future with regulators.

The FDA once put this drug on hold, causing GlaxoSmithKline to edge away from their collaboration on the drug. But GSK still has an option to grab marketing rights on the therapy, as Ionis pushes ahead with plans to file for an approval.

The efficacy data weren’t spelled out in the company’s statement. But the safety record was.

Dr. Morie Gertz

Researchers said that there were three serious cases of thrombocytopenia, or low platelet levels, that were triggered by the drug. One of those patients died from an intracranial hemorrhage. There were also two serious renal adverse events, and two other patients had to stop treatment following renal observations that raised investigators’ concerns.

That seemed to dictate the response among investors as Ionis shares slid 10% in pre-market trading.o140

On the positive side, there was clearly positive efficacy data on the Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy over the 15-month study. That helps explain why 95% of the 80% of patients who completed the study went on to continue therapy in the extension part of the trial.

Leerink’s Paul Matteis sized up the good, the bad and the ugly thus:

The efficacy results, which show a benefit on a disease specific scale (mNIS+7) AND quality-of-life, are better than investor expectations as the Street was more cautious on the latter measure. However, the safety of TTRrx remains a major question; IONS noted that “a detailed review of safety data from the study is ongoing”, and in the press release, the company reported cases of serious thrombocytopenia and a death due to intracranial hemorrhage.

That could all play out to Alnylam’s benefit. Its lead late-stage drug patisiran could prove a safer alternative to Ionis’ drug, which is why the Cambridge-based biotech’s shares shot up 15% this morning.

When the safety issue first came up last year, triggering the hold, GSK opted to shelve plans for a Phase III study of TTR amyloid cardiomyopathy.

Transthyretin — or TTR — amyloidosis is characterized by the gradual accumulation of amyloid in tissue and organs that lead to death.

Ionis’ stock was hit last week when an FDA warning letter was circulated highlighting the case of an investigator in a separate study who failed to properly test platelet levels in patients. Some of the analysts following the company noted that it raised some serious issues on safety related to its real-world use — how could physicians be expected to monitor platelet levels effectively if researchers don’t — and the stock, subject to repeated short attacks, took a hit. That issue will likely to be closely considered by regulators and outside experts during the drug review process.

“Familial amyloid polyneuropathy is a devastating genetic disease that is painful and rapidly progressive leading to early death. The positive results from the NEURO-TTR study today are very encouraging for this underserved patient population,” said  Dr. Morie Gertz, Division of Hematology, Roland Seidler Jr. Professor Department of Medicine. “I have been treating patients with this disabling disease for many years, and I am excited about the promise that inotersen holds to restore their lives. I believe inotersen has the potential to transform the current standard of care for patients with TTR amyloidosis.”

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