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February 8, 2013 3:06 pm

Lilly/Boehringer remain coy on insulin glargine’s EU, FDA regulatory strategies

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This article is provided to readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market.


Eli Lilly (NYSE:LLY) and Germany-based Boehringer Ingelheim will potentially have mixed regulatory strategies for LY2963016 (insulin glargine) in diabetes, experts told BioPharm Insight. The drug could be designated as a biosimilar in some territories, noted a Lilly spokesperson. She declined to specify the EU strategy but said some type of New Drug Application (NDA) will be filed in the US.

Biosimilars are produced in a manner that renders their effects similar to brand-name biologics and are thus deemed to be acceptable forms of the original biotherapeutics by regulatory agencies.

It is unclear whether LY2963016 is a true biosimilar, as the company could have slightly changed the formulation to sidestep patent issues, experts said. The Phase III asset is still, however, the same as glargine structurally, they noted. The drug has the same amino acid sequence as Sanofi’s (EPA:SAN) Lantus (insulin glargine), the spokesperson confirmed, but declined to explain differences between the two.

Lilly could submit LY2963016 to US and EU regulatory authorities in 2013, noted the spokesperson.

Positive results from LY2963016’s final Phase III trial are expected, experts told BioPharm Insight. The therapy is being tested in type 1 and type 2 diabetes. The type 1 diabetes study is estimated to complete in April 2013, while the type 2 diabetes trial finished in September 2012.

Lilly and Boehringer have guided to release data by 1Q13.

“We do not yet have decisions by regulatory bodies on how they will designate LY2963016,” the spokesperson noted.

Biologics are larger molecules and manufactured differently than traditional pharmaceuticals. Like generics for pharmaceuticals, biosimilars are expected to be less expensive than the originator biotherapies. Yet, the price difference will not be as big as the gap between pharmaceuticals and generics.

Lantus made EUR 4.96bn (USD 6.64bn) in 2012, up from EUR 3.92bn in 2011. LY2963016 is projected to make USD 482m by 2020, according to BioPharm Insight data.

To be similar or not to be

The assumption in the medical community is LY2963016 is a biosimilar based on the fact the amino acid sequence is the same as glargine, said an EU endocrinologist.

Yet, the endocrinologist noted, there could be formulation tweaks to give LY2963016 a different pH concentration, for example. Additionally, Lilly could offer a different concentration than glargine, he theorized. An EU diabetes expert added the formulation may be altered by the addition or amount of excipients.

Lilly could be considering new glargine indications, regimens or delivery devices, a second EU diabetes expert said. Or it may offer better tolerance or an improved pharmacokinetic (PK) profile, he added. PK refers to how the body uses the administered therapy.

The suspected improvements could make taking the therapy easier or result in fewer injections, less variability and longer shelf life, said Robert Bakin, patent agent/regulatory specialist, Technology & Business Law Advisors, Baltimore, Maryland. Such alterations could allow for Lilly to avoid possible conflicts with Sanofi’s method-of-use or formulation patents, he explained.

Insulin is a smaller molecule than other biologics and is well defined, so is simpler to produce compared to other biologics, said a second EU endocrinologist. The production process may differ, so there can be differences in PK and pharmacodynamics (PD), but the general structure will be identical to the original, he said. A PD profile indicates the drug’s impact on the body.

If PK or PD is significantly better, then Lilly would file as a new drug, he said, because such a discrepancy means it would not qualify as a biosimilar.

EU strategy

Biosimilars are meant to have a quicker route to marketing approval, because the treatments are allowed to have a smaller clinical program. Lilly’s LY2963016 clinical program has more than satisfied the requirements for a biosimilar in Europe, said the first EU endocrinologist. The first EU diabetes expert agreed the data package looks to exceed what the European Medicines Agency requires of a biosimilar application. The second EU diabetes expert added the trial is looking for an outcome measure beyond immunogenicity, or the treatment’s ability to trigger an immune reaction, which is the standard measure for EU biosimilars.

The LY2963016 trials’ inclusion of heterogeneous populations and the use of one or two antihyperglycemics, make it a more difficult trial than a standard biosimilar trial, which usually has one comparator, the second diabetes expert continued. Moving from Phase I studies to Phase III trials is typical for biosimilars, he said.

Yet, he noted, typical biosimilar trials used to gain approval are safety studies that require maximum 300 patients; The LY2963016 trials combined included 1,000 patients. Thus, it is possible that LY2963016 may require a new marketing application, he said.

A third EU endocrinologist downplayed the likelihood of Lilly filing the insulin under an EU new biologics application, as regulatory authorities typically look for a program with roughly 4,000 patients.

Lilly may be exceeding biosimilar application requirements, he suggested, to give LY2963016 a stronger commercial foothold against Lantus. Lilly probably conducted such a large clinical program for two reasons, the first EU endocrinologist noted: Global studies began before US biosimilar requirements were clear, or Lilly felt doing more than needed would set a high bar for competitors.

There is no EU-approved biosimilar insulin. UK-based Marvel failed in developing a biosimilar insulin for Europe, the second diabetes expert noted. Impurities, manufacturing controls and nonequivalence in Phase I sunk the application.

US plans

There is nothing to stop Lilly submitting LY2963016 as a new drug in the US or Europe, assuming there are no patent issues, the first EU endocrinologist noted.

The Biologics Price Competition and Innovation (BPCI) Act, combined with the US Food and Drug Administration’s February 2012 guidance documents, seem to indicate biosimilars can only be developed for a reference product previously approved via a Biologics License Application (BLA), said a US-based regulatory consultant. The language would then exclude insulin and human growth hormone products, which have been approved as NDAs, he added. Lantus was approved via an NDA in April 2000.

For biologics, the BPCI Act states a 10-year period must pass before products are eligible for biosimilar status, the regulatory consultant added. It is likely Lilly will file as a 505(b)(2) with Lantus as the reference product, but a 505(b)(1) application that contains full reports of investigations of safety and effectiveness cannot be ruled out, he added. Both applications are types of NDAs.

It is possible that Lilly files a 505(b)(2), said a US-based scientist and regulatory expert, which also allows LY2963016 to have certain differences from the reference molecule. The scientist and second diabetes expert noted based on the Phase I and III trial information, Lilly seems to be pursuing the same indications as Lantus. This strategy further suggests to the scientist that the 505(b)(2) route is likely.

A 505(b)(1) filing appears possible based on the amount of studies conducted, but a 505(b)(2), which is done for a reformulation and provides three versus five years of market/data exclusivity is an option, Bakin said. The latter option allows Lilly to work around Lantus’ formulation patents, Bakin said. However, formulation patents can be invalidated much more easily than composition-of-matter patents, he noted.

The BPCI created an alternative approval pathway for biosimilars, called the 351(k), or abbreviated pathway but no company has used it to date, according to an FDA spokesperson.

Lilly’s market cap of USD 62.4bn


For more information or to inquire about a trial please email or call Americas: +1 212-500-1384 or Europe: 44 (0)20 7059 6202

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