FDA review recommends no approval for CHTP’s Northera

Chelsea Therapeutics (NASDAQ:CHTP) CEO Simon Pedder’s recent defense of drug candidate Northera omitted a key detail: The U.S. Food and Drug Administration reviewer for Northera recommended the agency not approve the drug.

Release of that finding as well as the reviewer’s safety and clinical trial concerns now cast questions on a compound that was on the FDA’s fast track to address an unmet medical need for many Parkinson’s disease patients. Chelsea is scheduled to meet with an FDA advisory committee on Thursday to discuss Northera. While that committee’s vote is advisory, FDA approval of Northera now looks far from a certainty. The FDA released Northera briefing documents this morning.

Pedder spoke about Northera at the BIO CEO and Investor Conference in New York last week — before the FDA briefing documents were made public. He acknowledged FDA questions about safety and the short duration of the clinical trials. But he said the studies showed the drug had a statistically significant effect and that adverse events observed in patients treated with Northera were not definitively linked to the compound. While he acknowledged that 19 patients died in the Northera clinical trials, he said that most of those deaths were attributed to other causes. But at the conference, Pedder stopped short of disclosing that the FDA review recommended against Northera’s approval.

Chelsea, a Charlotte, North Carolina company, is developing Northera to treat dizziness and fainting in Parkinson’s disease patients due to a sudden drop in blood pressure upon standing. The condition is called neurogenic orthostatic hypotension, or NOH. The reason the FDA granted Northera orphan drug status and priority review is that there are few NOH treatments and some of the medications patients take off-label carry safety risks. The compound that Chelsea calls Northera has been used by patients in Japan since 1989 as droxidopa. Chelsea licensed droxidopa from Japan-based Sumitomo Pharma.

Northera only had one successful clinical trial. That’s sufficient under certain circumstances and the FDA indicated it would be enough for Northera: The drug was studied under a special protocol assessment in which the company reached an agreement with the FDA that success in one trial might be sufficient for approval. But despite statistically significant results in one trial, the review raised concern about the duration of the treatment. Northera’s effects weren’t shown to last longer than four weeks.

The review also raised safety concerns. The review notes that the low number of patients in the study exposed to the drug for long term — particularly at the highest dose — makes it difficult to gauge Northera’s long-term safety. Since NOH is an orphan indication, Northera might not have trials of the size and duration of other conditions. But the review said “this wouldn’t have been so problematic except that the safety of droxidopa was not so clean.” Adverse events, including deaths, were observed during longer-term studies. Among the top concerns in the review were reports in Japan of neuroleptic malignant syndrome — a rare but sometimes fatal disorder related to neuroleptic drugs. Pedder pointed to a 10-year post marketing safety study conducted in Japan. But the FDA review said it’s difficult to interpret data from uncontrolled studies and spontaneously reported events.

The findings suggest the need for additional Northera studies, at least in the eyes of the FDA reviewer. If the FDA issues a complete response letter on Northera, Chelsea will need to spend more time and more money to study Northera. And Parkinson’s patients who were waiting for a new NOH treatment that they thought was on the FDA fast track will have to wait longer.

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