Generic Lovenox In EU Will Require Clinical Data, Shrinking Sandoz’s Opportunity

An EU guidance issued earlier this year requiring clinical trials for generic copies of low molecular weight heparins may just have shot the European market opportunity for Momenta and its partner Sandoz, according to Momenta's CFO Rick Shea.

In an interview, Shea declared that "having a requirement for clinical studies in the EU potentially eliminates any differentiation you could obtain by virtue of superior characterization technology."

The leading branded LMWH product, Sanofi Aventis' clot-buster Lovenox (enoxaparin), sold €2.7 billion ($3.8 billion) in 2008. Its patent protection runs until 2012, but generics have been waiting outside the door for some time. Teva and Amphastar both filed ANDAs in the U.S. in 2003 while Momenta/Sandoz filed their ANDA for M-enoxaparin two years later.

Momenta claims that its technology - comprising enzymes to break down complex drugs into measurable units, improved analytical techniques and advanced mathematical data integration - allows near-perfect characterization of complex sugars like LMWH, as well as of protein-based mixtures and complex antibody drugs.

But since the EU guidelines don't appear to tailor trial size requirements, or indeed any other quantitative or qualitative aspect of trials, to the degree of characterization of the product, "it really levels the playing field," Shea explained, removing any potential advantage conferred by the technology, and thus "changing the potential rate of return" [on the product].

The decision as to whether to even file M-enoxaparin in the EU is Sandoz's. The Swiss giant signed an initial deal with Momenta around the heparin-based drug in 2003, and three years later expanded this into a broader co-development and co-marketing alliance covering three further compounds, including a generic version of Teva's multiple sclerosis drug Copaxone (glatiramer); one of the four has since been dropped.

Sandoz wouldn't comment on whether it will launch in the EU and what its clinical trial strategy might be if it does. Instead, a spokesperson was keen to emphasize that "we see absolutely no connection between the situation in the EU and our U.S. ANDA."

Indeed, the fact that FDA is reviewing M-enoxaparin under the 505(j) generic pathway shows that it's treating the drug more like a regular, small-molecule generic than as a biosimilar, as the EU appears to be doing.

LMWHs are somewhat of a halfway house, however. They're not proteins, but they're highly complex compounds, and, as the EU guidance argues in justification of their categorization, their starting material is biological: LMWHs are prepared from unfractionated porcine heparin, using chemical or enzymatic depolymerisation processes.

The EU has been a first mover with biosimilar regulation more broadly - its guidance on principles for biologics appeared in 2006, whereas the U.S. has yet to establish an approval pathway for follow-on biologics. But the EU's LMWH guidance may put the region on the backfoot with regard to promoting access to cheaper versions of the particular medicines.

Does EMEA Have a Clinical Bias?

The EU guidelines on LMWH "seem very clinically biased," opines Shea, "rather than allowing for the fact that you might have the ability to do more work on the chemistry side." In this sense, the guidelines mirror those published by the EMEA for other categories of biologics including biosimilar erythropoietin, growth hormone, insulin and granulocyte colony stimulating factor (G-CSF).

The guidance states that "because the heterogeneity of LMWH is very high, the mode of action not completely understood, and it is uncertain whether PD [pharmacodynamic] markers are representative for clinical outcome, the major burden of demonstrating that two LMWHs are similar biological products is on a clinical trial."

Besides PK/PD trials in healthy volunteers, the guidance calls for biosimilar drugs to prove therapeutic equivalence to the branded product in "at least one adequately-powered, randomized, double-blind parallel group trial," ideally in the setting of prevention of venous thromboembolism in high-risk patients undergoing surgery.

The European Generic Medicines Association also describes the LMWH clinical data requirements as "excessive for this class of medicines." Senior Director of Scientific Affairs Suzette Cox questions to what extent, if at all, the EU approach was discussed with FDA within the framework of the "transatlantic dialogue." "I understand any new guideline [on either side] is discussed by both agencies," she says.

The reason for the clinical bias within the EU guidelines - in contrast to the ANDA route deemed appropriate for LMWH drugs in the U.S. - may be organizational, suggests Shea. FDA has a longer history with a separate division for substitutable generic drugs, and with granting AB ratings and allowing interchangeability, he says.

At EMEA there is no separate organization geared specifically to approving generic drugs, nor is there an analogous AB rating system. It's left up to member states to decide whether a particular drug is substitutable.

The result may be that EMEA reviewers are more comfortable reviewing clinical data than working on the assumption that proof of chemical equivalence is sufficient, Shea surmises.

Such an attitude has implications for the follow-on biologics pathway in the U.S. if it is established. Early indications are that abbreviated BLAs will not be handled by a separate office like small-molecule ANDAs are currently, but the reviews of ABLAs will be undertaken by the review divisions with responsibility for the innovator product.

If the European experience is any guide, ABLA sponsors could face more clinical requirements than they may have initially been expecting.

A Contradiction?

Whatever the reason for the EU clinical trial requirements, it's unclear that they will actually help address the most important risk associated with heparin-based drugs: heparin-induced thrombocytopenia. This occurs when the immune system forms antibodies against heparin, leading to further clot formation and thus a low platelet count.

The heparin-induced thrombocytopenia risk may have been a driver behind FDA's November 2007 request to Sandoz for more in vivo immunogenicity data, to which Sandoz responded with further non-clinical safety data in November 2008 (¹ 'The Pink Sheet' DAILY, Nov. 5, 2008).

With regard to heparin-induced thrombocytopenia, the EU guidelines state that "monitoring of platelet count and an adequate diagnostic procedure in patients developing thrombocytopenia or thromboembolism during the trial has to be performed."

But "there's a major contradiction here," says Shea. "They're going to require clinical studies, but ... studies that fundamentally don't have any statistical significance." The trials won't be large enough to pick up thrombocytopenia cases since the condition only develops in a tiny proportion of patients (roughly 5 in 1,000). It would require a multi-thousand patient trial to pick that up.

The EU guidance doesn't state specific patient numbers for the required trials but clearly they're not expecting 15,000-patient studies.

Thus the trials that are performed will likely only reveal very major issues with a drug (other than heparin-induced thrombocytopenia). Those issues, in Momenta's opinion, would be reliably revealed in chemical characterization and other non-clinical techniques that Shea claims are far more precise. "Our view is that a clinical study ... is a very blunt instrument. Human patients are variable," he says.

A U.S. Opportunity for Sandoz

Sanofi - already trying to fend off a tide of EU generics of its top-selling heart drug Plavix (clopidogrel) - is likely very pleased with the EU guidelines as they may help stave off competition at least in this market. In its presentations the company clearly classifies Lovenox as a biologic, stressing the drug's complex structure (² 'The Pink Sheet,' Aug. 18, 2008, p. 8).

Sanofi has not been so fortunate in the U.S. The company in May 2008 lost an IP court battle and its patents were formally rendered non-enforceable in October 2008. That triggered Amphastar's 180-day exclusivity period, which expired on April 1.

Sandoz will focus attention on the U.S., where, with the IP fight settled in its favor, it expects to launch M-enoxaparin this year. The company also insists that concerns raised last year over contaminated heparin supplies from China - resulting in FDA warning letters to two Chinese producers in April (³ 'The Pink Sheet' DAILY, April 23, 2009) - will not impact the ANDA. "Our ability to analyze supplies for any impurities is well-respected within the FDA," a spokesperson said.

All four suppliers of M-enoxaparin have now been inspected and no concerns mentioned by FDA, according to Joseph Schwartz, an analyst at Leerink Swann.

Schwartz and other analysts appear unworried by the possibility that Momenta may lose the EU market - which is anyway less attractive than the U.S., given lower pricing. Schwartz's model does not include ex-U.S. revenues for the drug.

But if EMEA issues similar guidelines for MS drug glatiramer, these could, together with LMWH, provide a bigger blow to the Momenta/Sandoz pipeline. Their generic version of Copaxone has been accepted for review in the US under the 505(j) pathway. But in Europe, according to Shea, "it wouldn't surprise me if they [European authorities] followed the approach they're taking with LMWH," in other words, with a demand for clinical trials.

If indeed glatiramer is classified as a biologic, it will be subject to EMEA's general guidelines on biosimilar drugs, which state that "usually comparative clinical trials will be necessary." (⁴ 'The Pink Sheet', March 13, 2006, p. 13). According to EMEA's Biosimilar Medicinal Products Working Party's 2009 workplan, guidance on biosimilar glatiramer specifically isn't forecast, but discussions around individual products are confidential in any case.

- Melanie Senior (m.senior @elsevier.com)

This article also appeared in "The Pink Sheet" – June 15, 2009

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