Aripiprazole Lauroxil - USA

On Aug. 29, 2017, a Court of appeal for the District of Columbia upheld the Food and Drug Administration’s approval of a competitor for a major drug Aripiprazole. The two drugs at issue in this case are antipsychotics primarily used to treat schizophrenia and bipolar disorder. The first drug, manufactured by Otsuka Pharmaceutical, is called Abilify Maintena (Aripiprazole) injection. The second, made by Alkermes, is named Aristada (Aripiprazole Lauroxil) injection.

On Aug. 22, 2014, Alkermes submitted 505 (b)(2) application for Aristada, another injectable antipsychotic. The company also sought to rely on prior studies conducted by Otsuka demonstrating the safety and efficacy of Abilify Tablets. Aristada shares certain chemical similarities with the Abilify line of products: Aristada’s active moiety, N-hydroxymethyl aripiprazole, is a “prodrug” of aripiprazole, meaning that it ultimately metabolizes into aripiprazole in the body.

When Alkermes sought FDA approval for Aristada, Otsuka opposed the application on the ground that Aristada’s approval would violate an ongoing period of marketing exclusivity enjoyed by Abilify Maintena. Otsuka emphasized that both drugs ultimately metabolize in the body into the same molecule & in light of the relationship between the two drugs, approving Aristada would infringe on Abilify Maintena’s exclusivity. The FDA rejected Otsuka’s arguments and granted approval to Aristada. The agency relied on the fact that the two products have different “active moieties”—roughly active ingredients. In approving Aristada, the FDA staked out the position that a drug’s active moiety not only determines its eligibility for marketing exclusivity, but also defines the field of drugs subject to that exclusivity. Otsuka sought judicial review, contending, among other things, that the agency’s same-moiety limitation on the scope of a drug’s marketing exclusivity conflicts with the FDCA. The district court granted summary judgment in favor of the FDA and Alkermes. The court concluded that the FDA’s same-moiety test is a reasonable construction of the statute and is consistent with the agency’s regulations.

During appeal Otsuka based its argument on “legal equivalence” theory & argued that Aristada and Abilify Maintena are legally equivalent. Aristada relied in its application on Abilify Tablets, which in turn is legally equivalent to Abilify Maintena because the two drugs share the same active moiety (aripiprazole), and also because Abilify Maintena itself relied on Abilify Tablets for approval.

Appeal court rejected Otsuka’s “legal equivalence” theory and affirmed FDA’s “same-moiety” theory. Court said that statute nowhere expressly set out any concept of legal equivalence in describing the scope of marketing exclusivity. Congress perhaps could have written a statute under which, if one drug relies on the safety or efficacy of a previously approved drug to obtain approval, the two drugs must be considered “legally equivalent” for purposes of defining the previously approved drug’s zone of exclusivity. Relying on its decision in Actavis Elizabeth LLC v. FDA, 625 F.3d 760 (D.C. Cir. 2010) which involved prodrugs (which, as noted, are drugs that eventually metabolize into a different chemical compound in the body) court said that we have previously upheld the FDA’s understanding that a prodrug of a previously approved drug, if it has a different active moiety, can qualify as a “major innovation” entitled to “‘[N]ew [C]hemical [E]ntity’ status and the resulting five-year exclusivity” . In the FDA’s view, ”prodrugs with previously unapproved active moieties “are ‘major innovations’ deserving five-year exclusivity,” even if they ultimately metabolize into a previously approved active moiety. We have no occasion to revisit our decision in Actavis, or to question the FDA’s expert judgment that “even minor covalent structural changes are capable of producing . . . major changes in the activity of a drug.”

Finally appeal court said that for these reasons, Otsuka fails to show that the language of the FDCA unambiguously compels its “legal-equivalence” interpretation of the scope of marketing exclusivity under the romanettes. Rather, the agency’s “same-moiety” interpretation is reasonable and warrants our deference.