Biopharmacetiucal Approval Trends in 2009

The year 2009 bucked the trend of low biopharmaceutical approval numbers witnessed over the last several years. A total of 20 recombinant proteins and monoclonal antibody-based products were approved in the US or the EU over the year. These included seven antibody-based products, four erythropoietins or colony stimulating factors, two each of blood related products, hormones, and fusion proteins, as well as an interferon, a recombinant vaccine, and a bone morphogenetic protein-based product (Table 1). The increased approval numbers is welcome news indeed, although it remains to be seen if it represents a sustained upward trend or just a blip in annual approval rates. There are signs, however, that 2010 also will be a productive year, with 10 biopharmaceuticals having gained approval in the EU or the US by the end of June.

Gary Walsh

Cumulatively, 2009 approvals bring the total number of biopharmaceuticals approved to 200, and the overall 2009 global market value for biopharmaceuticals was estimated at $99 billion.¹

Absolute approval numbers, while providing an important indicator of the sector, do not provide a complete picture. Equally significant indicators include the number of approvals genuinely new to the market and their potential market value.

Fourteen of the 20 products approved in 2009 were genuinely new to the market. The other six, although newly approved in one region last year, had gained approval before 2009 in the other region (Table 1). Eight of the 14 new products contained genuinely novel active ingredients (Arzerra, Ilaris, Kalbitor, Removab, Roactemra, Simponi, Stelara, and Victoza) while six were biosimilars, reformulated, or "me too" products (Filgrastim hexal, Zarzio, Opgenra, Fertavid, Biopoin, and Eporatio).

Table 1. Biopharmaceuticals approved in the US or the European Union in 2009

Autoimmune or autoinflammatory conditions represented the principle target indication (seven products), while other target indications included cancer treatment or prevention (three products), anemia, neutropenia, and hereditary conditions (two products each), as well as infertility, diabetes, thrombocytopenia, and promotion of spinal fusion (single products in each case).

The predicted market potential for these new approvals—where data is available—is mixed. Reformulated or biosimilar products generally enter a competitive market place where they must fight for market share. For example, the European biosimilar market was estimated at $60 million in 2008, while the US biosimilar market is projected to reach a modest $30 million by 2013.² However, as more biopharmaceuticals come off patent and more biosimilars are commercialized, market share will grow, and some analysts predict that several individual biosimilar products will reach blockbuster status (>$1 billion in annual sales) before the end of the decade.

The market value of several of the genuinely new biopharmaceutical entities approved will likely be modest. For example, Kalbitor is indicated for the treatment of a rare genetic disorder (hereditary angioedema) and analysts predict sales to peak at approximately $150 million annually. On the other hand, sales of Simponi (an anti-TNF antibody indicated for rheumatoid and psoriatic arthritis) and of Victoza (a glucagon-like peptide receptor agonist indicated for type 2 diabetes) are each predicted to reach blockbuster status within the next few years.

In terms of expression systems used, 11 of the 20 approved biopharmaceuticals are produced using mammalian cell lines, five in E. coli, two in yeast (one each in S. cerevisiae and P. pastoris), and one each in an insect cell–based expression system and a transgenic system. These figures once again reflect the ongoing dominance of mammalian-based expression systems in biopharmaceutical manufacturing.

PRODUCT APPROVALS

The remainder of the article focuses on the 14 products approved for the first time in 2009. This information was drawn from regulatory sources and the web sites of sponsoring companies.^3,4 The remaining six products have been considered in previous articles.^5–7 Antibodies represented the single largest product class, with six such products (Arzerra, Ilaris, Removab, Acterma, Simponi, and Stelara) gaining approval in 2009. Produced in Sp2/0, NS0, or Chinese hamster ovary (CHO) cell lines, all antibodies are engineered in some way—four are fully human, one is humanized, and one (Removab) is particularly noteworthy in that it is the first bispecific antibody approved for human use.

Antibodies

Removab (catumaxomab) was approved in the EU in April 2009 for the treatment of malignant ascites (fluid accumulation in the peritoneal cavity) in patients displaying EpCAM-positive carcinomas. It remains in clinical trials for the treatment of various additional cancers, both in the EU and US. It is the first bispecific antibody to come on the market, i.e., unlike nativea antibodies, its two antigen-binding regions differ, thereby allowing it to bind to two different antigens. The antibody was developed and is manufactured by Trion Pharma (Munich, Germany), with Fresenius Biotech (Graefelfing, Germany) holding marketing authorization. The antibody comprises a mouse kappa light chain, a rat lambda light chain, a mouse IgG2a heavy chain, and a rat IgG2b heavy chain. The antibody displays two different antigen-binding sites, a mouse-derived epithelial cell adhesion (EpCAM)-binding Fab region and a rat-derived CD3-binding Fab region. EpCAM is overexpressed on the majority of epithelial tumors and the bispecific nature of the antibody effectively brings CD3 expressing T lymphocytes into close proximity with tumor cells. Additionally, the Fc region of the antibody facilitates docking of various immune effector cells (e.g., phagocytes and natural killer cells) which, in combination with the T lymphocytes, can induce tumor cell destruction. The product is administered by intraperitoneal infusion using a constant infusion pump system and the dosing schedule normally entails four separate infusions over 10 days. The main clinical trial investigating safety and efficacy entailed treatment of 258 patients with the product in combination with drainage of fluid from the abdomen versus the use of drainage alone. The main endpoint was lifespan without the need for further drainage. For patients treated with Removab, this averaged at 46 days, as opposed to 11 days in the case of patients treated with drainage alone. The most common side effects noted included lymphopenia (low lymphocyte count), abdominal pain, and digestive upset.

Arzerra (ofatumumab) gained approval in the US and the EU for the treatment of patients with chronic lymphocytic leukemia (CLL), which is refractory to fludarabine (a nucleoside analog) and alemtuzumab (Genzyme's anti-CD52 MAb, Campath). CLL, the most common form of leukemia in the US and EU, is characterized by accumulation of abnormal B-lymphocytes. Its course is highly variable with some patients never requiring treatment. However, approximately one third of sufferers develop an aggressive form from onset, requiring immediate attention. Current and past treatments include the use of alkylating agents and nucleoside analogs, as well as antibodies targeting B-lymphocytes—Campath (alemtuzumab) and Rituxan (rituximab). Arzerra is a 149 kDa fully human (IgG) MAb, generated by transgenic mouse and hybridoma technology, and produced in an NS0 cell line. It targets the CD20 antigen, which is expressed on the surface of both normal and transformed B-lymphocytes, but not on hematopoietic stem cells. Binding of the antibody to the cell surface induces lysis, likely by triggering complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The product is administered by infusion, with a dosage schedule of 12 infusions over a period of 28 weeks. The main clinical study supporting its approval was one trial involving 154 CLL patients, with just over half of patients to other treatments responding to Arzerra. The most common side effects noted included respiratory tract infection, neutropenia, and anemia. Arzerra is manufactured by GlaxoSmithKline (London, UK).

Ilaris (canakinumab) is a recombinant, fully human IgG expressed in Sp2/0 cells with binding specificity for human interleukin-1α (IL-1α). It was approved in both the US and EU for the treatment of Cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in persons four years of age and older. Autoinflammatory syndromes are usually underlined by aberrant regulation of cytokine signaling. CAPS (including FCAS and MWS) encompass one such group of rare autoinflammatory conditions, representing a spectrum of one disease manifesting with varying degrees of severity. The conditions are linked to mutations in a gene coding for a protein known as cryopyrin, which plays a role in the generation of free biologically active interleukin-1α (IL-1α). As a result, overproduction of IL-1α occurs, driving inflammation. General features of these conditions include recurrent fevers, rash, and joint pain. The discovery of the molecular basis of this disease group suggested the blocking of IL-1α activity as a potential treatment. Some CAPS patients have thus been treated with Kineret (anakinra, an IL-1 receptor antagonist approved for the treatment of rheumatoid arthritis since 2001), although that product's short half-life necessitates daily injections. Arcalyst (rilonacept; a soluble IL-1α decoy receptor) was approved for the treatment of CAPS in 2008. The fusion product's antibody Fc portion confers on it an extended half-life, supporting once weekly injections. The cited advantages of Ilaris over other treatments include a treatment schedule of one subcutaneous injection every eight weeks, as well as the inclusion of children in the approved indication. The main clinical study included 35 adults and children with CAPS. None of the patients receiving Ilaris over a 24-week treatment period experienced a relapse of symptoms (a disease flare), whereas 81% of patients receiving a placebo did experience a recurrence of disease symptoms. The most common side effects noted included inflammation of the nose and throat, and vertigo, as well as a potential for an increased risk of serious infection. Ilaris is manufactured by Novartis (Basel, Switzerland).

RoActemra (tocilizumab) is a humanized, 149 kDa antibody that binds specifically to the interleukin 6 receptor, preventing binding of IL-6, and effectively inhibiting the biological activity of this pro-inflammatory cytokine. It gained approval in the EU in January 2009 (and has subsequently been approved in the US in 2010 under the tradename Actemra). It is indicated (either as a monotherapy or in conjunction with disease-modifying anti-rheumatic drugs, such as the antimetabolite methotrexate), for the treatment of rheumatoid arthritis in patients who have had an inadequate response to certain other drugs. It usually is administered once monthly by infusion over 60 minutes. Product safety and efficacy was established by five main studies collectively involving >4,000 patients with moderate to severe rheumatoid arthritis, with the main endpoint measured being a reduction in symptoms of 20% or more, measured using a standard scale for rheumatoid arthritis. When given as an add-on to treatment therapies to which the patient exhibited an inadequate response, administration of RoActemra was between 4 and 9 times more likely to achieve a reduction in measured symptoms when compared to the administration of placebo. The main side effect of note is an increased risk of serious infections. RoActemra is manufactured by Roche (Basel, Switzerland).

Simponi (golimumab) is a 145 kDa fully human (IgG) MAb, generated by transgenic mouse technology, and produced in Sp2/0 cells. It targets human TNF-α, binding to both the soluble and transmembrane forms of this pro-inflammatory cytokine. It is approved in both the US and EU for the treatment of rheumatoid and psoriatic arthritis, as well as ankylosing spondylitis (inflammation in the joints of the spine). Binding to TNF prevents the latter from binding to the TNA receptor, thereby inhibiting TNF activity. It displays a mode of action similar to previously approved anti-TNF biopharmaceuticals (Remicade, Enbrel, Humira, and Cimzia). The product is supplied in the form of prefilled pens and syringes, and is administered subcutaneously once monthly. Safety and efficacy were established by five randomized, double-blind trials involving >2,000 participants, and in all cases treatment with Simponi significantly reduced the incidence and severity of disease symptoms. The most common side effect noted was upper respiratory tract infections. Simponi is manufactured by Centocor Ortho Biotech (Horsham, PA).

Stelara (ustekinumab) is a 149 kDa fully human (IgG) MAb produced in Sp2/0 cells. It specifically binds the p40 subunit of IL-12 and IL-23. It was approved in both the EU and the US in 2009, and is indicated for the treatment of adults with moderate to severe plaque psoriasis under certain conditions. It is administered by subcutaneous injection every 12 weeks. Psoriasis is a relatively common chronic inflammatory skin condition, affecting up to 3% of the general population. It is underlined by migration and over-activation of T lymphocytes in the epidermis, a process that is fueled in part by IL-12 and IL-23. By binding to these interleukins, Stelera prevents them from triggering a biological response. Safety and efficacy were studied in two main randomized, double blind, placebo-controlled studies, involving almost 2,000 adults with moderate to severe psoriasis. The primary endpoint measured was the proportion of sufferers who displayed a minimum response rate (an improvement of at least 75% relative to baseline when using the psoriasis area and sensitivity index). Almost 70% of sufferers receiving Stelara achieved such a response after 12 weeks, as compared to 3% of those receiving a placebo. The main potential side effect is an increased risk of infection. The trials are ongoing and are scheduled to last for up to five years. Stelara is manufactured in the US by Centocor Ortho Biotech (Horsham, PA) and in Europe by Janssen-Cilag (Antwerp, Belgium).

Products Other Than Antibodies

Kalbitor (ecallantide) is a 60 amino acid polypeptide produced by recombinant means in the yeast P. pastoris. It is the first approved biopharmaceutical to be produced in this particular recombinant system. Kalbitor was approved in December 2009 by the FDA for the treatment of acute attacks of hereditary angioedema (HAE). This genetic disorder is caused by mutations to the gene coding for the C1 esterase inhibitor, which plays a role in controlling the coagulation cascade in blood clotting, the complement cascade, and elements of the inflammatory process. The C1 esterase inhibitor is a major inhibitor of plasma kallikrein. The absence of active esterase inhibitor results in the overproduction of bradykinin. Bradykinin is a vasodilator believed to be primarily responsible for the episodes of painful swelling in various body tissues (usually lasting for several days) that characterize hereditary angioedema. Kalbitor functions by inhibiting plasma kallikrein, the plasma protease responsible for the production of bradykinin. The safety and efficacy of Kalbitor was primarily evaluated by two randomized, double-blind trials involving 143 HAE patients. The primary endpoints measured related to patient-assessed symptom severity and response scales, with Kalbotir scoring significantly better than the placebo. The most common adverse reactions noted included headache, nausea, and upper respiratory tract infection, while the most serious was the risk of anaphylaxis. Kalbitor is manufactured by Dyax Corporation (Cambridge, MA).

Victoza (liragutide) is a glucagon-like peptide 1 (GLP-1) receptor agonist produced by recombinant means in S. cerevisiae. It was approved in Europe in June 2009 for the treatment of type 2 diabetes (and has subsequently been approved in the US in January 2010). The product has an amino acid sequence identical to native GLP-1, with one exception: lysine34 is substituted with an arginine. A 16 carbon fatty acid also has been attached to lysine26, by a glutamic acid spacer. This increases the molecule's plasma half-life from approximately 2 min to 13 h, allowing once daily administration by subcutaneous injection. The product potentiates glucose-dependent insulin secretion. The efficacy and safety were assessed in five double blind, randomized controlled clinical trials involving almost 4,000 type 2 diabetics. The primary endpoint measured was the level of glycosylated haemoglobin (HbA1c; an indicator of long-term blood glucose levels) present in the blood after 6 and 12 months. Victoza treatment, alone or in combination with additional diabetic therapies, resulted in mean decreases of HbA1c levels by 0.5–1.5%. The common side effects included hypoglycemia. Victoza is manufactured by Novo Nordisk (Bagsvaerd, Denmark).

Biopoin and Eporatio (epoetin theta) are tradenames of a recombinant human erythropoietin (EPO) produced in a CHO cell line. The 165 amino acid 30.6 kDa glycosylated product displays an identical amino acid sequence to native human EPO and, like the native molecule, displays 3 N-linked and 1 O-linked oligosaccharide side chains. The EPO is manufactured by Merckle Biotech (Ulm, Germany) and is marketed as Biopoin by CT Arzneimittel (Berlin, Germany) and as Eporatio by Ratiopharm (Ulm, Germany). It is approved under both tradenames for the treatment of anemia associated with chronic renal failure and chemotherapy in adults. It is marketed in prefilled syringes and can be administered subcutaneously or intravenously. The dosage regimes typically entail thrice weekly administration for several weeks ("correction" phase), followed by a "maintenance" phase entailing once, twice, or three times weekly administration. The exact dosage levels may have to be experimentally determined for individual patients. The safety and efficacy was assessed in four main studies of chronic renal failure patients (842 patients in total), as well as three studies (586 participants) of nonmyeloid cancer patients receiving chemotherapy. The changes in hemoglobin levels represented the primary endpoint assessed, with product administration being associated with appropriate mean increases. The most common side effect noted during trials was clot formation in some patients on dialysis.

Fertivid (follitropin beta) is a recombinant follicle stimulating hormone produced in CHO cells. Schering Plough gained marketing approval (with the agreement of Organon, see below) for the product from the EU in March 2009. It is manufactured by Organon (Oss, the Netherlands) and the product, along with its indications, is identical to Organon's Puregon. The product is used to treat certain forms of female infertility, as well as deficient spermatogenesis in the male and its approval was based on the regulatory data on Puregon.

Zarzio and Filgrastim Hexal (filgrastim) are trade names of a recombinant form of human G-CSF (granulocyte colony stimulating factor) produced in E. coli. The product is manufactured by Sandoz. Sandoz also markets the product as Zarzio, while Hexal markets it as filgrastim hexal. This filgrastim product differs from the endogenous molecule only in that it contains an additional N-terminal methionine residue (a consequence of the recombinant expression system used), and in that it is not glycosylated (the endogenous molecule contains a single O-linked oligosaccharide side chain). It is a biosimilar product, approved in Europe since February 2009, with Amgen's Neupogen having acted as the reference medicine. Its indication is identical to that of Neupogen—the treatment of neutropenia associated with chemotherapy and selected additional conditions such as advanced HIV infection. The administration usually is subcutaneous or by daily infusion over several days. The clinical comparability to the reference medicine was established over four studies involving 146 healthy volunteers, and both products achieved similar increases in blood neutrophil counts. The most common side effect was musculoskeletal pain.

Opgenra (eptotermin alfa) is a recombinant form of osteogenic protein-1 produced in CHO cells, manufactured by Howmedica International (Limerick, Ireland). It gained regulatory approval in Europe in February 2009 and is similar to a previously approved Stryker product (Osigraft/OP-1 implant), containing the same active ingredient. In addition to the osteogenic protein, the product contains bovine collagen and carmellose (carboxymethylcellulose). Opgenra is indicated for posterolateral lumbar spinal fusion in adults suffering from spondylolisthesis (vertebral displacement) when autograft has failed or is contraindicated, and the product is administered by direct surgical implant around the affected vertebrae. The active substance then initiates bone formation directly at the implanted site by recruitment and activation of bone forming chondroblast and osteoblast cells. The collagen provides an appropriate support scaffold for these cells, while the carmellose generates a putty-like consistency, aiding product implanting. The safety and efficacy were assessed primarily in one main study involving 336 patients, and treatment with Opgenra was compared to direct bone autograft. Opgenera treatment was judged successful in 39% of patients, as compared to a 49% success rate in the case of autograft. Despite the lower efficacy, the product was approved for the treatment of individuals when autograft has failed or is contraindicated. The most common side effect associated with Opgenra application was bone formation outside of the fusion area.

Gary Walsh, PhD, is an associate professor in the Industrial Biochemistry Program at the University of Limerick, gary.walsh@ul.ie He is also a member of BioPharm International's editorial advisory board.

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