A district court shot down Sanofi-Aventis's arguments against FDA approval of Sandoz's generic Lovenox (enoxaparin). It found that the agency had the right to require Sandoz to conduct additional immunogenicity studies of its version of the anticoagulant and to permit Sandoz to use a different manufacturing process than Sanofi.

In an Aug. 25 order, Judge Emmet Sullivan of the U.S. District Court for the District of Columbia denied Sanofi's request for a preliminary injunction to overturn FDA's approval of Sandoz's enoxaparin ANDA. FDA approved the product on July 23 and Sanofi filed suit against the agency three days later ('The Pink Sheet' DAILY, July 27, 2010). The case will proceed, however, despite the ruling on the preliminary injunction.

While the decision is a victory for Sandoz and its marketing partner Momenta, it could also be good news for companies developing biosimilars. Although Lovenox is not a biologic, it is a complex compound that raises some of the same safety, efficacy and comparability issues involved in approval of follow-on biologics. Judge Sullivan backed FDA's rationale for approving Sandoz's product.

For Sanofi, the ruling is gut-wrenching, since it means the company's chances of halting generic competition through legal maneuvering are grim, though not entirely done in. Lovenox is Sanofi's second best-seller. In 2009, the blood thinner generated U.S. net sales of approximately $2.5 billion. Sandoz launched its generic in the U.S. immediately after receiving FDA approval. It told the court it expects to ring up sales of more than $40 million in the next six weeks.

Facing the loss of Lovenox and several other key drugs to generic competition in the near-term, Sanofi is looking to acquisitions to buffer its top-line. The company reportedly made a bid for the U.S. biotech Genzyme on Aug. 2, offering around $70 per share, although the speculation has not been confirmed ('The Pink Sheet' DAILY, Aug. 3, 2010).

But merger talks appear to have stalled, with Genzyme said to be balking at the offer. Many biotech analysts contend that Genzyme could sell for significantly more, around $80 per share. Rodman & Renshaw analyst Simos Simeonidis, in an Aug. 26 research note, said the court ruling could put more pressure on Sanofi to speed up talks with Genzyme and go "straight to more meaningful discussions about the price of a potential transaction."

Immunogenicity Studies Are Not Equivalent To Clinical Trials

Meanwhile, Sanofi's legal maneuver to block generic Lovenox could provide a lesson for other companies seeking to challenge FDA approvals. One of Sanofi's key arguments was that since FDA required Sandoz to submit additional tests on its product, the application should have been treated as a full new drug application and not an ANDA.

FDA required Sandoz to submit three types of studies comparing the immunogenicity (the potential to elicit an immune response) of its product with Lovenox. They included a comparison of the ability of the two products to bind to and form complexes with chemokine PF4 and characterization of the size and charge of the resulting complexes; studies to understand the amount and nature of potential contaminants; and functional studies to assess potential immunogenic properties.

The court states in a footnote that "while Sanofi repeatedly attempts to characterize the FDA's request for additional data on immunogenicity as impermissible 'safety testing,' the FDA explains that '[t]he additional data sought from Sandoz in this case was limited solely to assuring that Sandoz's manufacturing process would not produce impurities with potential immunogenic effects to any greater degree than Lovenox itself."

"Contrary to Sanofi's implication, FDA did not request or demand anything approaching the type of large-scale clinical safety and efficacy trials mandated for new drugs," the court said.

The court also rejected Sanofi's claim that FDA departed from its precedent in approving ANDAs for complex products not fully characterized. The company had cited the agency's past decisions for hyaluronidase, Omnitrope and Premarin . For example, for Premain the agency could not find active ingredient sameness for synthetic versions of the drug. FDA had argued that its finding of active ingredient sameness is specific to each active ingredient ('The Pink Sheet,' Aug. 2, 2010). The court said FDA provided legitimate reasons for deciding that enoxparain should be treated differently than the drugs Sanofi cited.

FDA's Test For "Sameness" Is Reasonable

Sanofi had also argued that since Lovenox is not fully characterized - i.e., all the structures within the drug have not been identified - it is impossible to tell if a generic has the same active ingredients. But the court said FDA's five-part test for determining "sameness" is reasonable. These criteria include equivalence of physical and chemical properties and equivalence of certain aspects of the drug's effect in humans.

"It was similarly reasonable for the FDA to conclude that an ANDA applicant need not use the same manufacturing process as Sanofi," the court stated.

The court rejected Sanofi's claim that it would face irreparable harm if Sandoz is able to continue to market its generic. It said Sandoz would also face significant harm if the court imposed an injunction and that the negative impact on both is "essentially 'a wash.'"

Despite its strong rejection of Sanofi's arguments, the court left the door open for further litigation. "This opinion does not foreclose the possibility that upon a more developed record, Sanofi may be able to establish that there are grounds for overturning the grant of Sandoz's ANDA," Sullivan said.

Brenda Sandburg (b.sandburg@elsevier.com)

Court Backs FDA Rationale For Approving Generic Lovenox

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