Biosimilar and Biobetter Scenarios for the US and Europe: What Should We Expect?

Abstract

We explore differences between biosimilars and conventional small molecule pharmaceutical generic drugs with respect to development, regulatory requirements, legal challenges, pricing and related market dynamics over the product life cycle, and compare these dynamics in the U.S. and Europe. We also address issues concerning the development, manufacturing and marketing of biobetters as well as biosimilars. After identifying a number of measurement issues involving quantification of medicine utilization volumes, using IMS MIDAS™ data we quantify adoption of biosimilars in nine European countries between 2006 and 2012. We discuss factors affecting investment decisions among traditional novel pharmaceuticals, novel biologics, biosimilars and biobetters, and describe various strategies recently employed by biopharmaceutical firms. We conclude by considering issues involving immunogenicity of biologics, as well as controversies regarding whether biosimilars should have identical international non-proprietary names as the reference brand.

Ernst R. Berndt is the Louis E. Seley Professor in Applied Economics, and Mark R. Trusheim is Visiting Scientist, both at the Massachusetts Institute of Technology, Alfred P. Sloan School of Management, Cambridge, Massachusetts, USA.

Appendix

Biologic Molecules with Biosimilar Entry in Europe and Elsewhere

Short-Acting Epoietin Recombinant (Erythropoietin, Alpha, Beta, Theta, Zeta)

According to the US Food and Drug Administration, “Erythropoietin is a glycoprotein whose main function is to stimulate the proliferation and differentiation of erythroid precursors in the bone marrow. Erythropoietin is produced mainly in the kidneys, though several other tissues produce lesser amounts of the growth factor.”⁶⁸ Approved by the FDA on June 1, 1989, Epogen/Procrit (epoetinalfa) was produced in Chinese Hamster Ovary cells that have modified through recombinant DNA technology to encode the gene for human erythropoietin, and was initially approved for the treatment of anemia in patients with chronic renal failure. Epogen/Procrit was subsequently approved for the treatment of anemia due to ziduvodine therapy in HIV-infected patients (1991) and for the treatment of anemia in patients with non-myeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy (1993). Both these supplemental approvals were based on demonstration of a reduction in the proportion of patients receiving shaded blood cell (RBC) transfusions.

Within Europe, the epoietin alpha reference product is Johnson & Johnson’s Erypo or Eprex. As of June 2011, there were five approved biosimilar products: Binocrit (Sandoz/Novartis), Epo A (Hexal/Novartis), Abseamed (Medici), Retacrit (Hospira) and Silapo (Stada), all approved between August 28, 2007 and December 18, 2007.⁶⁹ Using the IMS Health classification scheme, there are two non-referenced products in the epoietin biosimilar accessible market (defined as an original product, granted market exclusivity at the start of its commercial life in Europe, whose exclusivity is now expired, with the product never have been referenced, or may have been referenced but the referencing biosimilar has not yet launched): Roche’s NeoRecormon, and Teva’s Eporatio/Biopoin.⁷⁰ In the U.S., in addition to having been approved by the FDA for treating anemia in cancer patients on chemotherapy, anemia in chronic renal failure patients, and anemia in zidovudine-treated, HIV-infected patients, epoietin alfa is approved for the reduction of allogenic blood transfusion in surgery patients. As of 2011, Epogen/Procrit was available in 2000, 3000 and 4000 units/ml 1 ml single-dose vials for subcutaneous injection or intravenous solution administration, in 20000 units/ml 1 ml multidose vials, in 10000 units/ml 1 ml single-dose and 2 ml multidose vials, and in 40000 units/ml single-dose vials for subcutaneous injection or intravenous solution administration.

Another erythropoietin stimulating agent (ESA) approved in both the US and EU is Amgen’s darbepoetin alfa (brand name Aranesp in the US). Darbepoietin is distinguished from epoietin agents primarily because of Aranesp’s longer serum half-life, implying generally less frequent dosing than the epoietins.⁷¹ Currently Aranesp is patent-protected in the US and EU, with its earliest reported year of key US patent expiry being 2024; for Epogen this US patent expiry date is 2013.⁷²

Growth Hormone for Children Born Small for Gestational Age—SGA (Somatropin Molecule)

Of the approximately 2.5 % of children who are born small for gestational age (SGA), 10–15 % fail to “catch up” by age two. Children who do not catch up by age two, if left untreated, are destined in many cases to have compromised final height, relative to the norm for the population. A relative height measure is SDS—the number of standard deviations an individual at a particular age is away from the age-specific population mean. Though there are differences across and within countries on the measure of SDS triggering treatment, growth hormone supplementation in children born SGA can enhance growth velocity, height SDS, and predicted adult height. Aside from the known adverse effects of growth hormone therapy, of concern in treating these children is a risk of accelerating bone age beyond chronological age, with the possibility of precipitating precocious puberty and compromising final stature on that basis.⁷³

On August 24, 1995, the FDA approved Pharmacia and Upjohn’s NDA # 020280 application for Genotropin (somatropin recombinant) for children born SGA who fail to manifest catch-up growth by 2 years of age, caused by an inadequate secretion of endogenous growth hormone. Over the years the FDA has approved a number of supplemental indications (e.g., growth failure associated with chronic renal insufficiency, with Noonan syndrome, with Prader-Willi syndrome, with Turner syndrome, in adults with either adult- or childhood-onset growth hormone deficiency, and others) as well as several related somatropin products, such as Omnitrope (Sandoz), Serostim (Serono), Humatrope (Eli Lilly), Nutropin (Genentech), Salzen (Serono), Tev-Tropin (Gate), HumatroPen (Eli Lilly), Zorbtive (Serono), Norditropin (Novo Nordisk), Accretropin (Cangene), and Nutropin AQ, Nutropin AQ NuSpin 5, NuSpin 10 and NuSpin 20 (Genentech). Most of these formulations are subcutaneous injection, lyophilized power for solution, although some products, such as Norditropin, involve pen or two-chamber cartridge delivery systems, with a reconstitution device used to mix the diluent and powder.⁷⁴ Somatropin must not be injected intravenously. Genotropin lyophilized powder contains somatropin of rDNA origin, a polypeptide hormone. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin). Genotropin is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.⁷⁵

According to IMS Health, as of June 2011 both Pfizer’s (who acquired rights with the acquisition of Pharmacia and Upjohn) Genotropin and Eli Lilly’s Humatrope were reference products, the two approved biosimilar products were Novartis Sandoz’ Omnitrope and Somatropin (unknown manufacturing laboratory), whereas the non-referenced products included Sanofi Aventis’ Maxomat, Nova Nordisk’s Norditropin, Ipsen’s Nutropinaq, Merck Serono’s Saizen, and Ferring’s Zomacton.⁷⁶

Granulocyte-Colony Stimulating Factor (G-CSF), Filgrastim and Lenograstim Molecules

On February 20, 1991, the US FDA approved Amgen’s filgrastim (trade name Neupogen) to decrease the incidence of infection, as manifested in febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever. On April 2, 1998, the FDA granted a supplemental NDA approval for acute myeloid leukemia (AML) adult patients receiving induction or consolidation chemotherapy, for reducing the time to neutrophil recovery and the duration of fever.⁷⁷ Other approved⁷⁸ uses of filgrastim include in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation, and for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Neutropenia is condition with an abnormally low number of neutrophils in the blood—the body’s primary cellular defense system against bacteria and fungi. Neutrophils also help heal wounds and ingest foreign debris, such as embedded splinters. People who have severe neutropenia (fewer than 500 neutrophils per microliter of blood) can rapidly succumb to infection because their bodies lack the means to fight the invading organisms. Neutrophils mature in the bone marrow in about 2 weeks. After entering the blood stream, they circulate for about 6 h, searching for infective organisms and other intruders. When they find one, they migrate into the tissues, attach themselves to the intruders, and produce toxic substances that kill and digest the intruders. This reaction may damage healthy tissue in the area of the infection. The entire process produces an inflammatory response in the infected area, which appears on the body’s surface as redness, swelling, and heat. Neutropenia has several causes. The number of neutrophils can decrease because bone marrow production isn’t adequate or because large numbers of white blood cells are destroyed in the circulation. Aplastic anemia, and certain rare genetic diseases such as infantile genetic agranulocytosis and familial neutropenia cause decreases in the number of white blood cells. Certain drugs, especially chemotherapies used in cancer treatment, impair the bone marrow’s ability to produce neutrophils. Growth factors that stimulate the production of white blood cells, particularly granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can eliminate neutropenic episodes in cyclic neutropenia.⁷⁹

In the U.S., Neupogen is still marketed exclusively by Amgen. Four dosage forms are approved—two in single use vials, and two as pre-filled injectable syringes. Neupogen is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA analysis, except for the addition of an N-terminal methionine necessary for expression in E coli. Because Neupogen is produced in E coli, the product is non-glycosylated and thus differs from G-CSF isolated from a human cell. Neupogen is a sterile, clear, colorless preservative-free liquid for parenteral administration. In order to maintain clinical benefit, chronic daily administration is required.⁸⁰

A second form of recombinant human granulocyte colony-stimulating factor is lenograstim (brand name Granocyte, Chugai Pharmaceuticals, marketed in the EU by Sanofi Aventis), a Chinese hamster ovary-derived G-CSF, indistinguishable from native G-CSF, and differing from filgrastim which is an Escherichica coli-derived G-CSF and is non-glycosylated, having an extra methionine group at the N-terminal end of the peptide chain.⁸¹ Granocyte (lenograstim) is not available in the U.S., but is a non-referenced product in the EU, having brand names in addition to Sanofi Aventis’ Granocyte, Euprotin (Almirall), Myelostim (Italfarmaco) and Roche’s Neutrogin. As of June 2011, a number of biosimilars were approved in the EU using Amgen’s filgrastim (Neupogen) as the reference product. These biosimilars include a Biograstim (CT Arzzneimittel), Novartis’/Sandoz filgrastim Zarzio, Teva’s Tevagrastim, Ratiopharm’s Ratiograstim, Hexai’s Filgrastim Hexal, and Hospira’s Nivestim, all approved between September 15, 2008 and June 8, 2010.⁸²

Neulasta (pegfilgrastim) is a second-generation injectable granulocyte colony stimulating factor approved in both the US and EU. Pegfilgrastim is distinguished from filgrastim agents primarily because of pegfilgrastim’s longer serum half-life, implying generally less frequent dosing than the filgrastims. Specifically, whereas filgrastim requires daily dosing, pegfilgrastim is administered only once per chemotherapy cycle.⁸³ Currently Neulasta is patent-protected in the US and EU. According to Grabowski (2013, Slide 5), while the earliest reported year of key US patent expiry is 2013 for Amgen’s Neupogen, for its Neulasta it is 2015.

Infliximab (Remicade)

The EMA’s Committee on Human Medicinal Products (CHMP) approved Hospira’s biosimilar application for infliximab (injection) on September 10, 2013 with Centocor’s (Johnson & Johnson) Remicade serving as the reference product. Infliximib is a monoclonal antibody, an immunomodulator distributed as a lyophilized powder for solution. In the EU it is approved for treating ankylosing spondylitis (a chronic inflammatory disease of unknown origin, first affecting the spine and adjacent structures and commonly progressing to eventual fusion of the involved joints⁸⁴), psoriatic arthritis and psoriasis (see Table 1 in main text). In addition to these three indications, in the U.S. infliximab (Remicade) is approved by the FDA for treatment of Crohn disease, fistulizing Crohn disease, rheumatoic arthritis, and ulcerative colitis.⁸⁵ Infliximab is the first monoclonal antibody approved as a biosimilar in the EU. Like several other immunologic agents, infliximab has a risk of serious infections, since patients treated with infliximab are at an increased risk for developing serious infections that may lead to hospitalization or death. According to Drug Facts and Figures (2011, p. 2822), “Most patients who developed those infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.”

Since EMA approval of biosimilar infliximab (referenced to Remicade) occurred just several months ago, data on its uptake within EU countries are not yet available. Indeed, it is likely that Hospira has not yet obtained reimbursement approval from any of the EMA member countries.

Follitropin Alfa (Gonal-F)

The EMA’s Committee on Human Medicinal Products (CHMP) approved Teva’s biosimilar application for follitropin alfa (injection) on September 27, 2013 with Merck Serono’s Gonal-F serving as the reference product. Follitropin alfa is a human follicle stimulating hormone (FSH) distributed as a sterile, clear solution for subcutaneous injection. In the EU it is approved for treating an ovulation (the failure of the ovaries to release an egg during an ovulation cycle⁸⁶), stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilization (IVF), gemete intra-fallopian transfer and zygote intra-fallopian transfer, and for ovaleap in association with a luteisising hormone (LH) preparation for women with severe LH and FSH deficiency. It is also approved in the EU for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotropic hypogonadism with concomitant human chorionic gonadotropin (hCG) therapy.⁸⁷ In the U.S. follitropin alfa FDA approved indications are limited to an ovulation and ART treatments.⁸⁸ Follitropin alfa is the first fertility biosimilar approved in the EU.

Since EMA approval of biosimilar follitropin alfa (referenced to Gonal-F) occurred just several months ago, data on its uptake within EU countries are not yet available. Indeed, it is likely that Teva has not yet obtained reimbursement approval from any of the EMA member countries.