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For want of a nail

Delays for Horizant RLS drug provide lessons on bringing repurposed drugs to FDA

See Sidebar: Horizons beyond Horizant

FDA's handling of an NDA for Horizant gabapentin enacarbil looked like exactly the kind of thing that provides grist to critics who say the agency is needlessly delaying access to effective new medicines.

Whether the delays were necessary or needless, the lesson for companies developing new products based on old drugs is this: In a new treatment setting, FDA may demand that any safety risk, however remote, be addressed prior to approval.

If either the agency or partners XenoPort Inc. and GlaxoSmithKline plc had identified the potential for a problem earlier, Horizant likely could have been available more than a year ago.

Following 17 months of delays related to questions about the drug's safety, Horizant finally received approval from FDA to treat restless legs syndrome (RLS) on April 6.

Some of those delays, such as a 90-day review extension triggered by submission of a proposed REMS, can be attributed to procedural requirements, according to Russell Katz, director of FDA's Division of Neurology Products.

But the longest delay was caused by questions about studies that showed an increase in a rare type of tumor in rats known for decades to be associated with Horizant's active ingredient, the epilepsy drug gabapentin (see BioCentury, Feb. 22, 2010).

While these tumors have not been reported in humans taking gabapentin, Katz said the rarity of the cancer in humans, a lack of understanding of the mechanism of tumor development in rats, and limitations of the data available through the Adverse Events Reporting System (AERS) raised questions about Horizant's risk-benefit profile for the new indication of RLS.

Though these seem to be the very kinds of questions FDA's advisory committees are made to answer, Katz said the agency could not complete its thinking on the potential for carcinogenicity in time to prepare for a panel meeting, so the agency issued a complete response letter instead.

During the nearly 14 months it took the partners to prepare and FDA to review the response, it was not part of FDA's remit to worry that XenoPort lost nearly half its market cap and was forced to lay off half

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