Merck Emend Drug Interaction Studies Advised By Cmte., Approval Supported

Merck's Emend should be studied in combination with CYP3A4 substrate chemotherapy drugs for potential drug-drug interactions, FDA's Gastrointestinal Drugs Advisory Committee agreed during its March 6 review.

Committee members expressed concern about a potential safety signal in a small number of patients taking an Emend emesis regimen with three CYP3A4 substrate chemotherapy drugs (etoposide, vinorelbine and paclitaxel), as well as a lack of sufficient safety data for concomitant use with six other substrates.

The committee voted nine to three with one abstention that the available data on the first three chemo drugs were sufficient to support Emend (aprepitant) approval, but strongly recommended additional studies.

For the remaining six drugs (docetaxel, vinblastine, vincristine, ifosfamide, irinotecan and imatinib), the committee unanimously agreed data did not exist to support safe use with Emend. [For a ¹ webcast or video replay of this meeting visit FDAAdvisoryCommittee.com.]

Despite the potential safety issues, members expressed excitement at the potential for a new anti-emetic, and voted unanimously that Emend was shown to be effective in the prevention of vomiting and nausea.

Oncologic Drugs Advisory Committee member Otis Brawley, MD, Emory University, underscored the need for better anti-emetics. "I see a lot of patients who vomit an awful lot, even with the drugs that we currently have...and they need something better. I see here something that sounds like it's better."

If approved, Emend (formerly MK-869) would be the first agent approved for the delayed phase of emesis (25-120 hours post chemotherapy); other anti-emetics are indicated only for the acute phase (up to 24 hours). Emend has a novel mechanism of action that blocks substance P at the neurokinin-1 receptor in the brain.

Merck's proposed indication is: "Emend, in combination with other antiemetic agents...for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin."

FDA expressed concern about Emend use with CYP3A4 substrate drugs because of an increased incidence in serious adverse events seen in clinical trials. Emend is an inhibitor of the CYP3A4 pathway.

In Phase III studies, patients on the aprepitant regimen and a CYP3A4 substrate chemo drug experienced more cases of neutropenia and infection-related diseases than the comparator group. The trials studied Emend plus GlaxoSmithKline's 5-HT3 antagonist Zofran (ondansetron) and the corticosteroid dexamethasone, versus Zofran and dexamethasone alone.

There were eight cases of neutropenia out of 266 Emend patients (3%), versus two cases out of 251 patients on standard therapy (1%). Emend patients also reported three cases of septic shock, one case of sepsis and one case of upper respiratory infection, versus no cases in patients on standard therapy.

FDA acknowledged that the adverse events occurred in a very small number of patients, but maintained that their severity and the fact that some were only seen in the Emend patient group were causes for concern.

"This might represent a small signal that we could not define," FDA Gastrointestinal & Coagulation Drug Products Division Gary Della'Zanna said. "One of my concerns was some of these respiratory serious adverse events, as well as the incidence of infections."

"The numbers are very small, however, the numbers that were serious, infection-related adverse events were only seen in the aprepitant group," Della'Zanna said. "From that, I wasn't necessarily looking for condemning the use...just the committee's opinion on whether additional information was necessary."

Voting committee consultant and NIH National Heart, Lung & Blood Institute statistician Michael Prochan, MD, articulated the dilemma caused by the small numbers: "It's impossible from this data to say, okay it's harmful. Likewise, I think it's impossible to rule out harm."

"There hasn't been sufficient data to establish safety, but it might be very hard to have sufficient data to establish to a high degree of certainly that it's safe," Prochan said. He added that establishing safety may require studies involving thousands of patients.

The need for additional safety studies was more clear-cut for the other six CYP3A4 substrates; Merck presented little or no controlled data on concomitant use with docetaxel, vinblastine, vincristine, ifosfamide, irinotecan or imatinib.

Citing the difficulties Merck has had in enrolling patients in an ongoing docetaxel study (one patient is enrolled every two to three months), committee members recommended that the additional studies not hold up Emend approval.

"If it's impossible to do these studies, this drug...looks to be an important advance, and I would not want this drug held up for this issue," voting committee consultant Howard McLeod, Washington University, declared.

Committee member David Metz, MD, University of Pennsylvania, agreed, saying: "You are right to raise the concern, I would hate to see the patients who are clearly going to benefit from an important advance limited because of theoretic worries that we have about where we want to come down on our votes."

The discussion was reminiscent of the risk management considerations FDA's gastrointestinal division has faced in recent years, particularly the public backlash from the withdrawal and restricted re-entry of GSK's Lotronex (alosetron) (² (Also see "GSK Lotronex Plan Follows Accutane Model; Relaunch “Months” Away" - Pink Sheet, 10 Jun, 2002.), p. 3).

"The reason why we're airing this is because we want the public to know that we have discussed this," FDA Office of Drug Evaluation III Director Florence Houn, MD, told the committee.

"So when the agency gets criticized that we didn't look carefully, that they only have enough patients in these three drugs, why are you giving it broad labeling for everything, we want to say...we are aware of those issues, and we brought it to the public's attention."

Houn asked committee members whether they felt there was a potential for off-label use of Emend.

"When a new drug comes to market, particularly one that's been shown to be effective, doctors will tend to generalize and expand the indications," Ronald Fogel, MD, Henry Ford Hospital, said. "You may find that there are doctors that will use this for nausea and vomiting that's not chemotherapy-related."

The potential for off-label use is one reason for bolded labeling on the safety data and approved uses, members said. "The only thing a general practitioner looks at is the bold print....I would put something like this in bold print," Robert Levine, MD, State University Hospital, recommended.

Merck is proposing an unbolded statement in the precautions section of labeling: "Emend should be used with caution in patients receiving concomitant medicinal products that are primarily metabolized through CYP3A4; some chemotherapy drugs are metabolized through CYP3A4."

The company submitted two Phase III studies to support the indication; the primary endpoint was absence of emesis and no use of rescue therapy. In the first trial, 72.7% patients on the Emend regimen were responders, versus 52.3% on standard therapy. In the second, 62.7% of Emend patients were responders, versus 43.3%.

Some committee members questioned whether Merck adequately demonstrated nausea prevention, since some of the nausea-specific endpoints failed to reach statistical significance.

Merck argued that the results may have been confounded by the use of nausea rescue therapy. The company noted that a higher proportion of patients in the standard therapy group used rescue therapy: 27.6% versus 18% for Emend.

The committee also recommended that Emend be used in combination with any 5-HT3 antagonist, despite the fact that Merck did not study aprepitant in combination with all 5-HT3 antagonist dosage forms.

Merck provided exposure data for GSK's intravenous Zofran and Roche's oral Kytril (granisetron); Zofran was the only 5-HT3 antagonist used during Phase III. Another marketed antiemetic in the class is Aventis' Anzemet (dolasetron).

FDA expressed concern that pharmacokinetic data could not be extrapolated from I.V. to oral Zofran, and asked the committee whether additional PK studies were needed. The committee voted nine to three with one abstention that the available exposure data could be expanded to other 5-HT3 antagonist dosage forms.

Emend's three-day dosing regimen is administered in a 125 mg loading dose, followed by two doses of 80 mg.

Merck submitted the Emend NDA (21-549) on Sept. 27, 2002 and was granted priority review. The drug is in Phase III trials for depression.