The FDA's stance on generics - at least on versions of the blood thinner Lovenox, such as Momenta Pharmaceuticals Inc.'s M-Enoxaparin (and probably similar compounds from Teva Pharmaceuticals Industries Ltd. and Amphastar Pharmaceuticals Inc. - became somewhat clearer last week, sadly and surprisingly for hanging-on Momenta investors who watched the stock's value tumble 58 percent, closing at $5.67.

Word that the agency wants more immunogenicity data on M-Enoxaparin led CIBC World Markets to speculate that Momenta will need to conduct new trials, though company officials said questions might be resolved based on a more detailed characterization of enoxaparin plus reference to scientific literature.

Momenta and collaborator Sandoz Inc., the generics division of Novartis AG, started working on the product in 2003 and filed the abbreviated new drug application in the summer of 2005 for the version of low-molecular-weight heparin (LMWH), sold as market-leading Lovenox by Sanofi-Aventis. Sandoz last week got the not-approvable letter from the Office of Generic Drugs (which does not issue "approvable" letters).

Craig Wheeler, Momenta's CEO, said during a short-notice conference call Tuesday that the FDA said all applications - i.e., those submitted by Teva and Amphastar - will be required to deal with the potential for immunogenicity. "To this point in our application process, the agency has not asked any questions on immunogenicity prior to this letter," Wheeler emphasized.

Momenta remains "confident there should be no differences in immunogenicity" between M-Enoxaparin and Lovenox, Wheeler said. "What we are unsure of at this time is what the agency will be expecting of us to demonstrate that fact," he added, assuring investors that the firm believes it's "on a level playing field with the other applicants in addressing this issue."

Lovenox, the most widely prescribed heparin to prevent and treat blood clots, also is used in acute coronary syndromes, and Sanofi reaped worldwide sales of about $3.2 billion last year, with about $1.9 billion in the U.S.

Early this year, Momenta scored a court victory when the U.S. District Court invalidated Sanofi's key Lovenox patent for the second time, but shares reacted by plunging more than 20 percent, as investors seemed to believe Teva or Amphastar had an edge in the race to market. (See BioWorld Financial Watch, Feb. 19, 2007)

Other heparins on the market, such as Pfizer Inc.'s Fragmin and Pharmion Corp.'s Innohep, capture relatively little share. Lovenox is the compound with which to show bioequivalence. About 72 percent of the overall heparin market belongs to Lovenox, and about 80 percent of LMWH, but the patent expires in 2012. Momenta hopes to achieve FDA clearance for M-Enoxaparin as a generic that can be directly substituted for the Sanofi compound.

The antithrombotics space is big business. Datamonitor forecasts sales to peak over $20 billion in 2012 across seven major markets, with growth driven by oral anticoagulants such as Bayer AG's Xarelto (rivaroxaban) and Boehringer Ingelheim AG's Rendix, expected to launch next year. But it was the slice occupied by Lovenox and its would-be generic competitors that drew attention from Wall Street last week.

CIBC predicted Momenta's stock would "settle in the $7 to $8 range, and [we] would be surprised if there was additional downside," according to a research report. Shares closed Wednesday at $5.32. Analysts at Deutsche Bank downgraded Momenta from "buy" to "hold." Rodman & Renshaw moved its rating from "market outperform" to "market perform."

In a research report, CIBC's Bret Holley wrote that, "while this is clearly a major setback for Momenta, we believe M-Enoxaparin would eventually make it to the market," and pointed to "value in the company's pipeline, including M118 and additional generic biologic programs."

One analyst during the conference call asked whether the FDA questions regarding M-Enoxaparin casts Momenta's technology platform in a bad light. "We do not believe that at all, at this point," Wheeler said. Another wanted to know whether pharmacokinetic and pharmacodynamic studies measured what the FDA is worried about.

Wheeler said results of the PK/PD studies have not been made public, but Momenta has plenty of data on hand but is "not sure how that's going to play into what's necessary for the agency" and "there are certainly multiple approaches we can take" to examine the immunogenicity issue. "What we don't know yet is what specifically is behind the agency's questions," Wheeler said.

The Momenta development with M-Enoxaparin comes amid governmental debate regarding how generic and follow-on products ought to be handled, and an analyst on the conference call wondered aloud whether the OGD letter might be a delaying tactic to put off deciding about generic heparin until larger matters are settled.

"There are a lot of interpretations [possible]," Wheeler said. "Clearly, this came late in the game for us, and I'm assuming probably also for other applicants, but we don't know that for sure. It's hard to speculate on motives at this time."

In any case, he said, the FDA apparently did not single out M-Enoxaparin

"We still believe - but of course that's all going to be proven out in conversations with the agency - that because we have the characterization data, and all the work that's been done in terms of process development and equivalence to the innovator, that it should be a leg up for us" in the march toward approval, Wheeler said.

How long it might take for M-Enoxaparin to get back on track is hard to say until Momenta knows what the FDA will require, which could mean more human trials. But "as we understand the process here, if we can adequately address the agency's concerns, we can amend the ANDA and continue the review" without needing to re-submit, and start again.

Rod Riedel, vice president of regulatory affairs, allowed that "one can imagine, depending upon the nature of the specific questions that the FDA has, a broad spectrum of activities," from in vitro work to a review of scientific literature to ex vivo work, including a non-clinical package or a new set of trials. "We'll have to be flexible about thinking about our response until we find out explicitly the issues that the FDA wants us to address," Riedel said.

Sandoz has paid for trials to this point, Wheeler said, but he couldn't say who would fund future studies, if needed. "I don't think we have a clear view, in terms of how that would work," he said. For now, the company is aimed at getting a meeting with the OGD for details about its concerns. Momenta has only the letter, and what officials were able to glean during phone conversations with the FDA related to disclosure.

"The call was made by us to various people at the agency to help us interpret what the letter meant," Wheeler said. "What we've given you is everything we've gotten from them."