Merck & Co. Inc. will enter its second advisory panel for anesthesia injection Bridion (sugammadex) July 18 armed with safety data submitted well in advance of the meeting, after an eleventh hour data submission tripped up the panel’s review of the drug in 2008.

FDA’s Anesthetic and Analgesic Drug Products advisory committee will review the novel agent, which reverses muscle relaxant effects after surgery, including a new safety study conducted by Merck at the request of the agency. During its first approval cycle, the same panel gave the drug a vote of confidence, though the committee meeting was complicated by a late submission of hypersensitivity data, so the panel did not make a formal recommendation for approval Also see "Schering-Plough’s Bridion Makes Positive Impression On Advisory Panel" - Pink Sheet, 11 March, 2008..

FDA ultimately deemed the drug “not approvable” in August 2008, due mostly to concerns of hypersensitivity/allergic reactions, Schering-Plough Corp, later acquired by Merck, said at the time Also see "Schering Plough’s Bridion Faces FDA Setback" - Pink Sheet, 1 August, 2008.. FDA also requested and the company submitted data related to coagulation (bleeding events) Merck said in January when it announced FDA’s acceptance of its resubmitted NDA.

The new hypersensitivity study found that 0.7% of patients receiving a 4 mg/kg dose of sugammadex had adjudicated hypersensitivity signs and symptoms, compared to 4.7% of patients receiving a 16 mg/kg dose and no patients who received placebo. The study randomized 448 participants who received one dose of treatment or placebo at day eight, day 36 and day 78. Ten patients in the 16 mg/kg treatment arm did not complete the study due to adverse events, compared to four patients in the 4 mg/kg arm and two patients in the placebo arm.

Two secondary endpoints examined the percentage of patients with adjudicated anaphylaxis based on two different definitions. One analysis, which looked at the percentage of participants with adjudicated anaphylaxis according to criteria defined by the Symposium on the Definition and Management of Anaphylaxis described by Sampson et al., found that 0.7% of patients in the 16 mg/kg sugammadex arm experienced anaphylaxis compared to no patients in the 4 mg/kg or placebo arms.

Another analysis, which looked at the percentage of participants with each of the three levels of diagnostic certainty of adjudicated anaphylaxis according to the definition by Rüggeberg et al., also found no patients in the 4 mg/kg arm or placebo arm experienced anaphylaxis while 0.7% of 16 mg/kg patients were adjudicated as level 1, the highest level of anaphylaxis certainty and 1.3% as level 2.

Patients in the 16 mg/kg arm also experienced more serious adverse events than those in the other two arms. Merck said it is confident in these new data and that it plans to pursue all doses of the drug including 2 mg/kg, 4 mg/kg and 16 mg/kg.

Merck announced March 14 that FDA will take an additional three months to review its resubmitted NDA, pushing the agency’s decision on the drug to the second half of 2013. Bridion, including a 16 mg/kg dose, has been approved in Europe since June 2008 Also see "Europe Likes Schering’s Bridion, But Not Takeda’s Rozerem" - Pink Sheet, 3 June, 2008..

The drug could be a marketing companion for Merck’s Zemuron (rocuronium), a nondepolarizing neuromuscular blocker used as an adjunct to general anesthesia to facilitate tracheal intubation Also see "Merck On Track To File Novel Sleep Aid Suvorexant In 2012" - Pink Sheet, 6 February, 2012..

Focus On Safety Surprised Analysts

At the time of the drug’s initial FDA rejection, analysts expressed surprise about FDA’s concern regarding the hypersensitivity events noting that in a controlled setting like the operating room such events might be controllable. Analysts also pointed out that the advisory committee did not mention the allergic reactions as a significant concern and hypersensitivity was not seen as an issue in pivotal trials. At the March 2008 meeting, the advisory panel did recommend post-marketing surveillance of hypersensitivity and requested more pediatric data.

The 2008 panel voted unanimously that the primary endpoint in the pivotal trial was clinically relevant. It also voted in favor of there being sufficient clinical evidence that the drug when used with rocuronium provides a clear advantage with Cannot Ventilate, Cannot Intubate scenarios.

Merck Comes Prepared This Time As Sugammadex Faces Second Advisory Committee

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