Copaxone And Complex Generics: Difficult-To-Copy Does Not Mean Impossible

FDA’s approval of the first ANDA for an MS therapy signals the agency’s determination to find a way to get generic versions of complex drugs to market. What if any lessons does that hold for biosimilars?

FDA’s approval of Sandoz Inc./Momenta Pharmaceuticals Inc. generic glatiramer acetate (Glatopa) reiterates the agency’s determination to find a way to approve copies of complex, difficult-to-copy drugs.

That’s the foundational message from the April 16 approval, and from the very substantive, simultaneous rejection of Teva Pharmaceutical Industries Ltd.’s citizen petition campaign to forestall generic competition to Copaxone 20 mg/1 ml.  “We recognize and have carefully considered the complexity of Copaxone,” FDA told Teva. “This complexity alone does not preclude a finding of active ingredient sameness between a generic glatiramer acetate injection and Copaxone.” (Also see "Copaxone Generics: FDA Approval Standards Defy Teva’s Argument On Complexity" - Pink Sheet, 27 Apr, 2015.)

The approval is obviously an important development in the MS marketplace, clearing the way for the first generic launch in what has become a large specialty drug class.

It has been a long time coming, and the wait is still not quite over.

The approval comes seven years after the ANDA was first submitted, and about five months ahead of the expiration date (September) for a contested Copaxone patent. Sandoz is responsible for determining when and if to launch the generic and has indemnified Momenta from any potential damages if the September patent is upheld. As of early June, Sandoz has not announced a launch for the generic, apparently awaiting further clarity in the litigation.

Mylan Pharmaceuticals Inc. also has an ANDA pending for a generic Copaxone, and the company has repeatedly declared that it expects to be approved at “market formation” for the generic market. FDA, however, has not yet cleared the Mylan product.

At the same time, Teva has moved a significant portion of the Copaxone market to a newer, three-times-per-week formulation. That will likely blunt some of the impact from the generic launch when it last it comes.

But the approval action in itself is an important marker of FDA’s ability to approve complex generic drugs, and will be read as a further indicator on the future of the emerging “biosimilar” class as well – even though glatiramer acetate is a synthesized copolymer and not regulated as a biologic.

FDA’s description of the basis of approval in its letter rejecting Teva’s eight petitions seeking to block generics is noteworthy on several levels, both asserting the agency’s ability to approve generics of very complex products while seeming to avoid laying out an exact “recipe” for other generic sponsors to follow.

It also emphasizes a bright statutory line between complex drugs and biologics – and the related standards for evidence for abbreviated filings – even if the molecular differences may not be so clear cut.

The Line Between “Drug” And “Biologic”

Unlike the approval five years ago for Momenta’s generic enoxaparin, this approval and FDA’s detailed explanation seems less broadly precedent-setting but more designed to reiterate the agency’s pertinacious approach to working with rigorous ANDA sponsors on difficult-to-characterize products.  (Also see "FDA's Balancing Act: Early Hints at a Biosimilars" - Pink Sheet, 1 Dec, 2010.)

The enoxaparin approval gave the first preview of how FDA might structure some of the required elements of a successful biosimilar application.

FDA only grudgingly accepted the reading of the enoxaparin approval as a biosimilar precedent – citing it as an example that very careful, cutting edge analytical work can provide a great deal of assurance that a candidate biosimilar does meet the threshold test for entering the abbreviated biologic development pathway. The Copaxone response can be read in the same way – albeit with less explicit discussion of exactly what analytic steps Momenta used to satisfy FDA in this case.

The more important nuance, however, may be in the opposite direction: FDA includes some quiet but firm declarations of the difference between the two abbreviated development paths with the key point being that glatiramer may be a complex molecule, but it is a “drug” and therefore subject to the ANDA route.

In a footnote, FDA notes “that several of Teva’s assertions in its Citizen Petitions seem to indicate that although regulated as a drug product, Copaxone is in many ways more like, or shares characteristics with, a biological product.” However, FDA continues, Copaxone is a listed drug approved under section 505(c) of the FD&C Act, and, thus, the ANDA approval pathway is available for generic glatiramer acetate injection. “

In other words, the path to an interchangeable designation is not solely a function of the complexity of the product – but also a function of which statute applies.

A second footnote further explains and justifies FDA’s definition of Copaxone as a drug: it may be constructed from amino acids, but it is not a “protein” and therefore not a biologic:

Although proteins are also composed of amino acids joined by peptide bonds, glatiramer acetate is distinguishable from proteins because (unlike a protein) it does not, as described above, have a defined and specific amino acid sequence.  Rather … in the glatiramer acetate mixture, there is a negligible likelihood of having identical amino acid sequences along entire copolymer chains from batch to batch. Conserved sequences in glatiramer acetate are instead limited to short amino acid sequences within the copolymer chain. Although these preserved local sequences may be reflected in analyses used to establish active ingredient sameness, there is also broader sequence variability inherent to Copaxone. As such, glatiramer acetate is best described not as a protein, but rather as a heterogeneous mixture of copolymers.

The line between drugs and biologics will become a more important issue for FDA and sponsors by the end of the decade: under the biosimilar law, FDA is supposed to reclassify products like insulin and human growth hormone that are currently regulated as NDAs as biologics. FDA’s legal staff has identified that transition process as a thorny issue for which it is now beginning to prepare. There are likely to be other cases where sponsors argue their “drug” should in fact be on the “biologics” track at FDA.

No Road Map For Other Generics

The Glatopa approval decision does suggest some of the difficulties for subsequent applicants for glatiramer generics. Momenta says it knows of three other ANDAs pending.

FDA noted, for instance, that ANDA applicants “would need to identify and analyze structural signatures that are chemical attributes of glatiramer acetate and correlate to both the polymerization step…and the cleavage step of partial depolymerization.”

FDA stresses that this will be an individual, sponsor-by-sponsor project. “We anticipate that each ANDA applicant will develop its own set of structural signatures for its generic product and will compare these signatures to” Copaxone (the reference drug). In a footnote, FDA further observed that the “signatures to be used in connection with glatiramer acetate are unique to glatiramer acetate and are more extensive than those used in connection with enoxaparin.”

With glatiramer, sponsors will have to do signature analyses at multiple steps of synthesis (including initiation, polymerization and partial depolymerization. With enoxaparin, the signature determination of “sameness criteria” focused “on one primary step of its synthesis (i.e. cleavage).”

Each applicant for glatiramer, FDA observed, will have to “provide information to support the validity of its proposed structural signatures and the corresponding methods.”

In a conference call after the approval was announced, Momenta CEO Craig Wheeler was quizzed about how much of the Momenta process would be proprietary. Without being specific, he noted that his company had made representations to FDA about how much of the enoxaparin process of characterization and testing was revealed in approval materials five years ago.

Wheeler noted that he felt that the agency had shown sensitivity to the issue of describing the Momenta glatiramer pathway too openly to other potential competitors. He praised the effort of FDA to explain how it had assured sameness while respecting the value of the process developed Momenta. Wheeler said the process of matching Copaxone is a pretty high hurdle.    

While Wheeler hopes that Momenta’s process for showing sameness will be difficult for other ANDA sponsors to reverse engineer from FDA’s CP petition denial document, FDA declares that Copaxone is amenable to re-engineering.

“Several of Teva’s assertions in its Citizen Petitions suggest that, given Copaxone’s complexity, its manufacturing process cannot be reverse-engineered.” FDA said flatly, “we disagree.” Sponsors can start with publicly available information regarding synthesis and couple that with “the sensitivity and diagnostic capabilities of the structural signatures.”

Three of the criteria for FDA approval of the ANDA relate to the composition of the active ingredient. A fourth component is a biological assay “as a confirmatory test of equivalence.” FDA finds that the best assay at this stage is a tested animal model, the EAE assay (experimental autoimmune/allergic encephalomyelitis assay). Teva had urged FDA to require several biochemical assays. However, FDA rejected that request in favor of the animal model test.

“Due to the variability” of the suggested biochemical tests, FDA noted, “and the narrow focus of a particular test compared to the broad potential mechanisms of action of glatiramer acetate, the result of any one such biochemical assay provide less information with respect to active ingredient sameness than the EAE assay.”

Credit To New FDA Quality Structure

Two elements of the approval timing are significant. First, FDA issued the approval the day after the agency issued a white paper that serves as a mission statement for the new Office of Pharmaceutical Quality.

Wheeler noted the important work of OPQ in the approval of Glatopa and said that he is “thrilled” at what is happening in that office.  Similarly, FDA cited the work of the new office and its predecessors in the long list of groups participating in the long review of the methods for determining sameness to glatiramer. 

The multiple references to the role of OPQ suggests that the new organizational structure at FDA, while separating some of the quality determination functions from the actual ANDA review effort, may serve to increase the proficiency of the science and confidence of the agency in tough-to-copy development projects. Overall, however, this was still a long process for Momenta: about eight years, comparable to the amount of time that it took the company to develop generic enoxaparin and convince FDA of the sameness of that drug (approved in 2010).

A second element of the timing may have a bigger commercial impact: FDA announced the Glatopa approval in time for the American Academy of Neurology annual meeting in DC (April 18-25). That will facilitate wide discussion of the new approval and how FDA determined equivalency.