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Nov 12, 2013

Following Up on Follow-On Biologics

Branded drugmakers boost biosimilars, but costs and red tape remain as challenges.

Following Up on Follow-On Biologics

Biosimilar sales have grown from $378 million in the year ending June 30, 2011, to an estimated $2.445 billion this year. [© Xuejun li - Fotolia.com]

  • Reinvigorated this year with the first new approvals in three years, Europe’s biosimilars market is heading into 2014 with prospects for more of the same, as branded drugmakers join the generics in launching new near-copies of aging blockbusters.

    Stada is gearing up to launch Grastofil (filgrastim), a cancer biosimilar of Amgen’s Neupogen®, under a license from Apotex following approval last month. Also, Hospira and Celltrion are preparing to introduce Inflectra (infliximab), their near-copy of Johnson & Johnson’s Remicade, whose European patents expire in 2015. Inflectra is one of two monoclonal-antibody biosimilars approved by European regulators this year; the other was Egis’ Remsima (infliximab). Like Remicade, the biosimilars are indicated for rheumatoid arthritis and other inflammatory conditions.

    Remsima, Inflectra, and Grastofil are three of four biosimilars authorized by the European Commission just this year; the fourth is Teva’s Ovaleap (follitropin alfa), its biosimilar of Merck Serono’s in vitro fertilization treatment Gonal-F. The four bring to 15 the number of biosimilars authorized in Europe. Among biosimilars vying to be #16 are the Eli Lilly/Boehringer Ingelheim biosimilar insulin glargine (LY-2963016), one of at least two biosimilars of Sanofi’s Lantus in the works; Mylan and Biocon are developing the other. Other brand drug companies are jumping in: Sanofi has launched Phase I studies for several insulin products, while Amgen in 2017 plans to launch biosimilars of Remicade as well as Humira, Avastin, Herceptin, Rituxan, and Erbitux.

    Whatever the new biosimilars make in sales it won’t likely be anywhere near the annual multi-billions enjoyed by blockbuster-branded biologics. Yet biosimilar sales have grown, from $378 million in the year ending June 30, 2011 (IMS Health), to an estimated $2.445 billion this year (Visiongain).

  • Obstacles Remain

    Until now, the highest hurdle to higher biosimilar sales has been slow acceptance by EMA and FDA, Michael Waterhouse, analyst, specialty pharmaceuticals with Morningstar, told GEN.

    “If I had to rank the importance, I think it’s more just getting the regulatory bodies comfortable with the safety of the products in the first place, getting through whatever clinical trials they need to. Then beyond that, you get into building physician confidence in using these products,” Waterhouse said.

    Many doctors have been reluctant to prescribe biosimilars, siding with some biopharmas dead-set against losing sales. AbbVie and InterMune sued EMA in March seeking to block release of their clinical trial data as commercially confidential. But biosimilar development has also been slowed by higher producing and handling costs, and the time and expense of additional clinical studies, preventing the scale of price savings seen with generics. Biosimilars cost only 20–30% less than their reference drugs, Erwin A. Blackstone, Ph.D., and Joseph P. Fuhr, Ph.D., said in a 2012 Biotechnology Healthcare study.

    Then there’s the ongoing dispute over biosimilar naming. Both sides restated familiar arguments last month at a World Health Organization (WHO) discussion forum: Brand biopharmas and their supporters seek distinct nonproprietary names—containing a common, shared root with distinct and differentiating suffixes—for biosimilars and other biologics. But generic and biosimilar drugmarkers and their supporters say there’s no reason to vary from the WHO’s International Nonproprietary Names (INN) convention, contending the combination of a unique brand name, manufacturer name, NDC code, and lot number ensures full traceability. They also note that biosimilars using the same INN as their reference products have been marketed in Europe since 2006, without problems.

    “The outcome of this debate will be critical to the future of the biosimilar industry in the U.S. in particular, but it is important to realize that what is at issue here is not the best way of managing a new situation, but a concerted attempt by certain influential parties to change a system that has already been successfully tried and tested in many highly regulated markets worldwide,” Chris Lewis, a Sandoz spokesman, told GEN.

    Sandoz, the generics unit of Novartis, dominates the global biosimilar market with a share of more than 50%. During the first nine months of 2013, Lewis said, Sandoz generated sales of $301 million, up 22% in constant currencies from a year earlier, from its three biosimilars—somatropin, filgrastim, and epoetin alpha.

    Sandoz is one of three top biosimilar developers in Europe, Waterhouse said; the others are Teva and Hospira. The small number of top players means smaller sales for every other company.

    “Even when you compare it to the typical generic product, a biosimilar is still a much more attractive opportunity for them, just because if you’re only looking at three competitors, it’s much different than when you have Lipitor going generic, and after the exclusivity period, you have 10 or 12 people coming into the market. And that’s just not something we see occurring in the biosimilar area,” Waterhouse said. “Most of these molecules will probably have maybe one, two, or three at most biosimilar competitors. In general, that would tend to uphold pricing much, much better than most generic drugs.”

    Developers will need those higher prices, since the cost of developing a biosimilar ranges from €100 million ($134 million) and €250 million ($334 million), according to the European Generic Medicines Association, versus just millions for generics (estimates vary based on complexity, from $1 million to $4 million [IMS, 2011] to $50 million [Datamonitor and Canada’s Better Pharmacare Coalition]). U.S. biosimilar development costs could rise higher, Waterhouse said, depending on how much FDA will ultimately require in clinical trials to show comparability, as well as where drug developers manufacture their products.

  • Biosimilars in the U.S.

    In the U.S., biosimilar drug developers continue to await final regulations, four years after a pathway was mandated, then attached to President Obama’s Affordable Care Act. FDA is nearing two years of reviews on three guidances issued in 2012 to address scientific and quality considerations, and answer common questions on biosimilar development. In March, FDA issued a fourth guidance covering formal meetings between the agency and biosimilar sponsors.

    “FDA is carefully reviewing and considering the comments submitted to the biosimilar draft guidance and public hearing dockets. We will take into consideration all comments as we move forward in finalizing the draft guidance documents and in developing future policies regarding biosimilar and interchangeable products,” FDA spokeswoman Lisa Kubaska, Pharm.D., told GEN on November 7.

    As of November 1, Dr. Kubaska said, FDA’s Center for Drug Evaluation and Research (CDER) received 57 requests for an initial meeting to discuss biosimilar development programs for 13 different reference products, and held 49 initial meetings with sponsors. CDER also received 18 INDs for biosimilar development programs, with additional development programs proceeding under a pre-IND.

    Absent U.S. regulation, Europe remains the global regulatory leader in biosimilars, having developed an approval pathway in 2005, and okayed its first drugs a year later. But quicker approvals in emerging markets (notably China and India) mean that Europe, Japan, and the U.S. accounted for just 20% of global biosimilar revenues, according to Visiongain. Over the next decade, the developed world will see faster growth, as U.S. regs emerge and biologic blockbuster patents expire. Drugs totaling $67 billion in sales will lose protection by 2020, says the Generics and Biosimilars Initiative.

  • Biosimilars in Europe

    Seeking further market growth, EMA earlier this year issued three draft guidelines covering biosimilars, quality issues, and nonclinical and clinical issues—the last of which is still open to public comment until November 30. The three will be finalized separately, EMA spokeswoman Sophie Labbé told GEN: “They have different timetables, and will be published separately in due course according to these.”

    “With the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an Applicant to compare the biosimilar in certain clinical studies and in vivo nonclinical studies (where needed) with a non-[European Economic Area] authorized comparator,” the draft biosimilar products guideline states.

    Any savings of effort from studying a non-EEA drug would largely disappear through proposed requirements that biosimilar developers ensure the non-EEA drug was authorized “by a regulatory authority with similar scientific and regulatory standards as EMA,” and submit studies with “structural and functional data comparing all three products” that “establish an acceptable bridge to the EEA-authorized reference product.”

    “Applicants will be responsible for establishing that batches sourced from outside the EEA are representative of the reference medicine authorized in the EEA through an extensive analytical comparison. Applicants may need to supply comparative pharmacokinetic and pharmacodynamic data to ascertain the suitability of batches of the reference medicines,” Labbé added.

    That proposed change has support from two industry groups that include branded and biosimilar drugmakers, European Biopharmaceutical Enterprises (EBE) and EuropaBio. "The revisions discussed offer important developments to further strengthen the biosimilars pathway in Europe,” said Eugene Corretge, strategic unit regulatory head at Sanofi, speaking for the groups at an October 31 EMA workshop.

    That bodes well for the draft guidelines being finalized in 2014, which in turn should further compel FDA to finalize its own draft guidances and finally expand the global biosimilars market to the U.S., which accounts for about half of all biologics sales (some $160 billion last year, according to IMS MIDAS)—and where a large population, plus pressure to cut sky-high drug prices and other healthcare costs, should equal long-term growth.



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