Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

As originators try to defend their patents, companies make larger investments in biosimilars.

Despite delays by the FDA and some opposition from originator companies, biosimilars now represent one of the most rapidly evolving areas of product development in the biopharmaceutical industry. The EU already has legislation in place for the approval of biosimilars, and the FDA has publicly committed to publishing biosimilar guidelines by the end of this year.

Judging from the feverish activity among potential biosimilar marketers, mAb follow-on proteins will be the hottest competitive area. At $6.6 billion in 2010 sales, Rituxan is the largest revenue-producing biologic yet to be targeted by biosimilar developers. This anti-CD20 chimeric mAb is approved for chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, and RA and is due to come off patent in 2015.

South Korea’s Celltrion has initiated clinical trials of CT-P13, its Rituxan biosimilar. Sandoz, Novartis’ genetics arm, has a Phase II RA trial with its own version of Rituxan. Teva Pharmaceuticals and Spectrum Pharmaceuticals are also working on Rituxan biosimilars; Teva obtained therapeutic protein production capacity and expertise through its 2009 joint venture agreement with Lonza focused on biosimilars.

A key motivation for these endeavors is the loss of patent protection in a number of countries for more than 30 branded biologics, with combined estimated annual sales of $51 billion, between 2011 and 2015. Thirteen key biologic products are set to lose U.S. patent protection by 2015. Amgen’s Epogen, a recombinant form of erythropoietin, and Neupogen, a recombinant human granulocyte-colony stimulating factor (G-CSF), lose patent protection in 2013.

The potential global market for biosimilars provides the fundamental substantive motivation for biopharma companies to develop and commercialize these molecules, especially in the face of their shriveling pipelines and blockbuster drugs like Lipitor coming off patent. According to Datamonitor, global sales of biosimilars reached $243 million in 2010 and are projected to grow to $3.7 billion in 2015.

Biosimilar Activity in the U.S.

U.S. pharma companies aren’t waiting around for FDA guidelines to pursue a biosimilars program. To date the FDA has not approved a biological product as a biosimilar or interchangeable. Since passage of the Affordable Care Act in 2010, however, the agency has been working on establishing standards.

Approval criteria for biosimilars will be based first on an evaluation of analytical similarity to an innovator. That evaluation will drive FDA’s requirements for clinical data.

On December 16, FDA held a public meeting to discuss its proposals for a biosimilar user fee program with stakeholders. FDA plans on collecting user fees equal to PDUFA fees and would do so from when an IND is filed as compared to when an NDA or BLA is filed in the case of PDUFA fees.

Like Teva big U.S. pharma companies have been investing in biosimilars development through acquisitions and collaborations. On December 6, Biogen Idec and Seoul-based conglomerate Samsung reported that they have joined forces to develop and market biosimilars, building on Samsung’s agreement with Quintiles. The two companies will form a joint venture that will be funded with $255 million from Samsung and $45 million from Biogen; Biogen will have a 15% stake in the venture.

Merck & Co. created its business unit Merck BioVentures (MBV) aimed at launching six or more follow-on biologics between 2012 and 2017. The JV is expected to spend $1.5 billion on biosimilar R&D through 2015 in order to meet its goal of putting at least five candidates into the clinic by the end of 2012, according to Frank Clyburn, svp and GM of the venture.

Merck Research Laboratories’ president Peter Kim said Merck would proceed without any expectation of a straightforward biosimilar process at FDA. Each of their products will be backed, he said, by extensive clinical studies including complete toxicology studies and Phase III trials. The unit anticipates filing a BLA for each biosimilar.

Merck & Co.’s acquired Insmed for $130 million to put it in the follow-on space. Merck gained two clinical-stage programs: a Neupogen follow-on called INS-19 currently in Phase III and a Neulasta biosimilar in Phase I known as INS-20. MBV also obtained preclinical versions of Epogen and an interferon-beta 1b molecule.

In addition, Merck acquired manufacturing capacity—a 50,000 square foot facility based in Boulder, CO. It offers yeast-fermentation capabilities essential to the glycosylation process Merck is using in the recombinant yeast technology it gained through its acquisition of GlycoFi in 2006. The platform, which forms the base of Merck’s biosimilars strategy, came to Merck through its 2006 purchase of GlycoFi for $400 million.

Zooming In on mAbs

Michael Kamarck, MBV president and svp of vaccines and biologics manufacturing, commenting on MBV’s most likely initial products, said, “Early on, so-called replacement products like EPO were the clear winners and darlings of the biopharmaceutical industry. However it is becoming increasingly evident that monoclonal antibodies and related antibody fusion proteins are going to be a bigger and more tactical part of MBV’s business going forward.”

Generally speaking, according to Kamarck, “The greatest commercial opportunities for molecules in the biosimilar space are ones that modulate immunity or treat various cancer indications.”

Biosimilar versions of mAbs for oncology indications will reach more than $4 billion in sales in the U.S., France, Germany, Italy, Spain, U.K., and Japan by 2020, according to Decision Resource. The same report also said that biosimilar versions of rituximab could be approved as early as 2013 in Europe.

Such a regulatory go-ahead will pave the way for biosimilar versions of other mAbs including Bristol-Myers Squibb/ImClone/Eli Lilly/Merck Serono’s Erbitux and Roche/Genentech/Chugai’s Herceptin andAvastin.

Will Originators Mimic Embrel?

Another major mAb therapeutic is Pfizer and Amgen’s Enbrel. This anti-TNF mAb is approved for a number of diseases including RA, psoriasis, and arthritis and goes off patent in October 2012. Merck is targeting Enbrel through a collaboration with Korean firm Hanwha Chemical.

A Phase III study under way in Korea is comparing Hanwha’s version of Enbrel called HD203 with Enbrel as combination therapy with methortrexate to treat RA. Clinical trials with HD203 have yet to be initiated in the U.S.

Under terms of the deal Merck will carry out clinical development and manufacturing of HD203 and has rights to commercialize the drug globally, except in Korea and Turkey, where Hanwha has retained marketing rights. The June deal committed Merck to paying up to $720 million for Hanwha’s copy of Enbrel.

At least in the case of Enbrel (etanercept), however, a real show stopper for biosimilar companies may have emerged that has nothing to do with the awaited regulatory guidelines. If the “submarine patent” principle holds, other torpedoes may lurk to thwart biosimilar antibody developers.

On November 22, Amgen reported that the patent for the fusion protein that is Enbrel (U.S. Patent No. 8,063,182) had just been extended by 17 years; Enbrel is owned by Roche and exclusively licensed to Amgen. Immunex, acquired by Amgen in 2002, originally licensed this patent application from Roche in 1999. In 2004, Amgen paid Roche a one-time fee and obtained an exclusive, fully paid-up license to the application.

In a statement to GEN, Amgen said, “we have patents related to particular methods of making Enbrel, Enbrel formulations, and methods of treatment that provide protection against Enbrel biosimilars. This newly issued patent to the fusion protein that is etanercept adds to that patent protection.

“We are confident in our ability to protect our products and, as we previously stated, we do not envision Enbrel biosimilar competition in the United States for the foreseeable future.”

An analysis by Geoffrey Porges and his group at Sanford C. Bernstein found that indeed Amgen has a formidable piece of IP to defend against the incursions of biosimilar competitors. The analysts said that based on conversations with the three involved parties, Roche, Amgen, and Pfizer, sunsetting of Amgen’s profit-sharing obligation on Enbrel to Pfizer in the 2013–2015 period is unaffected by this patent, and Roche is not entitled to any royalties on Enbrel now or in the future.

Enbrel had been talked about as one of the first complex biologics likely to appear in a biosimilar form, with protection assumed to expire in late 2012 in the U.S. and in 2015 in Europe. If Amgen’s patent sticks, it could keep Enbrel biosimilars off the market until at least 2028. Biosimilar companies with large stakes in antibody development, however, are still likely to challenge the ’182 patent or come up with ways to circumvent it.

While originator companies will look for ways to protect their patent turf, biosimilar firms will keep an eye on the potential profits to be had with these follow-on biologic products. We can expect companies to join forces as needed to gain a foothold in the market and battles that will provide good livings for lawyers for a long time to come.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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