Biopharmaceuticals: Approval Trends in 2008

The year 2008 was, like 2007, a somewhat disappointing year in terms of the number of new biopharmaceuticals approved. The year witnessed the approval of eight recombinant proteins or engineered antibody-based products in the US, and two such biopharmaceuticals in the European Union (EU, Table 1). These products included hormones, interferons, blood factors, and fusion proteins—two each—as well as one antibody-based product and a colony-stimulating factor.

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Although 10 approvals does not appear an unduly low number, only four of those products contained genuinely new active ingredients (Arcalyst, Cimzia, Nplate, and Recothrom; Table 1). Arcalyst and Nplate are fusion proteins, Cimzia is an antibody Fab', and Recothrom is a recombinant thrombin (blood coagulation factor IIa).

The other six (Accretropin, Extavia, Filgrastim ratiopharm, NovoLog mix, PEGintron/ribetol combo, and Xyntha) are effectively reformulated, biosimilar or "me too" versions of previously approved products (see sidebar: Biosimilar Products).

Biosimilar Products

Product indications too are somewhat diverse and none aim to treat cancer. Also notable amongst the 2008 crop is the paucity of antibody-based products. No full-length antibody came to the market last year, although one antigen-binding antibody fragment (Cimzia) did gain approval.

In terms of expression systems used, the 2008 approvals also appeared to buck the general trend toward mammalian-based systems. Six of the 10 approved products are expressed in E. coli, one in S. cerevisiae, and three in Chinese hamster ovary (CHO) cell lines. However, the E. coli bias is less obvious in the context of genuinely novel active pharmaceutical ingredients approved, of which two are expressed in E. coli and two in CHO cells.

In most previous years too, some overlap in EU and US approvals was evident.^1–4 Not so in 2008. Although approval numbers in the US were modest, they were even more disappointing in EU, with only two products coming on the market. Moreover, neither of the EU approvals (Extivia and Filgrastim Ratiopharm) were genuinely novel (see sidebar).

In financial terms too, the majority of products approved, are expected to generate modest as opposed to blockbuster-level revenues. Nplate, Xyntha, and Recthrom sales are each projected to reach the $300–500 million mark.⁵ Arcalyst, aimed at treating CAPS (Table 1) has designated orphan status. With an estimated total US population base of only 300–500 patients, the market potential has been estimated at $10–35 million, despite the drug's premium price (approximately €250,000 per patient annually).⁶

Table 1. Biopharmaceuticals (defined as recombinant proteins, monoclonal antibody, and nucleic acid-based products) approved in the US or EU in 2008

The only product with a likely potential of reaching blockbuster status is that of Cimzia.⁵ Although initially approved only for the treatment of Chron's disease, it was subsequently approved (May 2009) for the treatment of rheumatoid arthritis, greatly increasing its revenue scope.

Overall, therefore, 2008 was a modest year in terms of biopharmaceutical approvals. Analysts, however, are hopeful that this will represent a low point, with approvals likely to steadily increase once again in the coming years.⁵

Individual monographs for products are presented below. Monograph for Extavia, Novologmix 50:50, and PEGintron ribetol are not provided, given their particularly close similarity to well-established, previously approved products.

PRODUCTS APPROVED

Accretropin (somatropin) is a recombinant form of human growth hormone (hGH), expressed in E. coli. Native hGH is a 191 amino acid, 22kDa polypeptide hormone synthesized in the anterior pituitary and Accretropin is identical to the native molecule in amino acid sequence. Accretropin is a biosimilar-type product. It was approved in January 2008 under section 505 (b) of the food, drug, and cosmetic act—a similar route under which Sandoz's hGH product, Omnitrope, gained approval in 2006.

Accretropin is indicated for the treatment of pediatric patients displaying growth failure because of inadequate secretion of endogenous hGH and for short stature associated with Turner syndrome (a chromosomal disorder) in pediatric patients whose epiphyses (the rounded end of long bones) are not closed. Dosage regimes should be individualized for each patient, but normally entail daily subcutaneous administration of 0.18–0.36 mg/kg body weight. Safety and efficacy were assessed in two trials containing 44 patients with growth hormone deficiency and 37 patients with Turner syndrome, respectively. Clinical results confirmed accelerated growth (height velocity) and the most common adverse reactions related to injection site events including erythema, edema, and brusing.

Product manufacture is initiated by fermentation of the engineered E. coli. As initially synthesized, the recombinant product displays an additional N-terminal methionine residue, a consequence of the expression construct used. Subsequent to product recovery the additional methionine is cleaved, yielding a product identical in sequence to the native hormone. Additional downstream processing entails multistep chromatographic purification and sterile filtration. Final formulation entails the addition of NaCl, phenol, pluronic F-68 surfactant, and phosphate buffer constituents as excipients, and the product is presented in liquid solution (1 mL of a 5 mg/mL solution in glass vials). Accretropin is manufactured by Cangene corporation (Winnipeg, Canada) and is marketed in the US by Apotex, Cangene's majority shareholder.

Arcalyst (rilonacept) is an engineered dimeric fusion protein with each of its two constituent polypeptides consisting of the ligand-binding domains of the human interleukin-1 receptor (IL-R1) and interleukin 1 receptor accessory protein (IL-1RacP), linked to the constant (Fc) portion of human IgG1. The 251 kDa glycosylated product is expressed in an engineered CHO cell line. It was approved in February 2008 by the FDA for the treatment of cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), in persons 12 years 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 generating free biologically active interleukin-1 (IL-1β). As a result, overproduction of IL-1β 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-1β activity as a potential treatment. Some CAPS patients were thus 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 necessitated daily injections. Arcalyst also brings about its therapeutic effect by acting as a decoy receptor, binding excess free IL-1β, and hence, preventing it from interacting with cell-surface receptors. The product's antibody Fc portion confers on it an extended half-life, supporting once weekly injections.

Arcalyst's safety and efficacy profiles were established by a randomized, double-blind, placebo-controlled study involving 47 CAPS patients. Participants rated primary signs and symptoms of CAPS (joint pain, fever or chills, rash, eye pain or redness, and fatigue) on a scale of severity from 1–10, with Arcalyst-treated patients reporting a mean reduction in symptom severity of –2.4. Moreover, mean symptom scores subsequently increase when patients were withdrawn to placebo. The most common adverse reactions reported were injection-site reaction and an increased susceptibility to infections.

Arcalyst is manufactured and distributed by Regeneron Pharmaceuticals (New York, NY). Manufacture entails initial cell culture of the CHO producer cells, followed by chromatographic purification. The product is marketed in a lyophilized form and contains histidine, arginine glycine, sucrose, and polyethylene glycol as excipients.

Cimzia (certolizumab pegol) is a recombinant humanized anti-TNF-α antigen-binding (Fab') fragment covalently linked to a 40kDa polyethylene glycol. The 91 kDa antibody fragment is expressed in E. coli and is composed of a 214 amino acid light-chain and a 229 amino acid heavy-chain fragment. The FDA approved the product in April 2008 for the treatment of Crohn's disease in adult patients who have not responded adequately to conventional therapy.

Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract. Characteristic symptoms can include abdominal pain, diarrhea, vomiting, or weight loss. The condition is characterized by overactive T cell activity, including the overproduction of proinflammatory cytokines—most notably tumor necrosis factor-α (TNF-α). Cimzia brings about its therapeutic effect by binding (mopping up) TNF-α, thereby reducing the pro-inflammatory effect. Unlike additional full-length antibody-based therapies for Chron's disease (Remicade and Humira), Cimzia is devoid of the antibody Fc component, and therefore, cannot trigger Fc-mediated functions, such as complement fixation or antibody-dependant cell-mediated cytotoxicity. The PEG moiety extends the product's plasma half-life (antibody fragments are characterized by substantially shorter half-lives than intact antibodies), allowing an initial dosage regimen of once fortnightly subcutaneous injection, with subsequent once monthly maintenance dosages.

Product safety and efficacy was primarily established in two double-blind, randomized placebo-controlled studies with a combined population of over 1,000 Crohn's sufferers. Overall, the studies confirmed a statistically significant improvement in product-treated patients as compared to the placebo group. The most common—and potentially life threatening—adverse reactions were increased risk of infection, with tuberculosis, invasive fungal, and other opportunistic infections, all being observed in Cimiza-treated patients.

Manufacture entails chromatographic purification subsequent to product recovery from E. coli-based fermentation and the final product is formulated in a lyophilized form, containing sucrose, lactic acid, and polysorbate as excipients.

Filgrastim ratiopharm (filgrastim) is a recombinant form of the 174 amino acid native human granulocyte colony stimulating factor (G-CSF) expressed in E. coli. Compared to native G-CSF the product is nonglycosylated and contains an extra N-terminal methione reside, both modifications reflecting the recombinant expression system used. Approved for general medical use throughout the EU in September 2008, Filgrastim ratiopharm is a biosimilar product and the reference product against which it was compared was Amgen's Neupogen (also produced in E. coli, also nonglycosylated and of an identical amino acid sequence).

Filgrastim ratiopharm is indicated for reducing duration or incidence of neutropenia associated with certain conditions, including cancer therapeutic regimes, advanced HIV infection, and congenital neutropenia. Neutropenia is a condition triggered by a significant decrease in blood neutrophil (white blood cells capable of ingesting and destroying bacteria) levels and is characterized by the occurrence of frequent and usually serious infections. G-CSF functions as a growth and differentiation factor for neutrophils and their precursor cells, and activates mature neutrophils. Clinical comparability to Neupogen was investigated in one main trial involving 348 breast cancer patients suffering from severe chemotherapy-associated neutropenia and with follow-up safety assessments in patients with non-Hodgkin's lymphoma and lung cancer. Safety and efficacy were comparable to the reference medicine, with muscoskeletal pain representing the most common side effect recorded.

The active substance is manufactured by SICOR Biotech (Vilnius, Lithuania) with Ratiopharm (Ulm, Germany) holding the marketing licence. Manufacture entails initial fermentation of the producing E. coli, induction of product synethesis, and subsequent recovery of product-containing inclusion bodies from the harvested cells. The inclusion bodies are dissolved using a chaotrophic agent, with protein refolding then undertaken in a reducing–oxidizing system. The product is then purified to homogeniety by column chromatography. The final product contains sorbitol, polysorbate, and sodium acetate buffer components as excipients and it is presented in solution in prefilled syringes.

Nplate (romiplostim) is a dimeric fusion product. Each of its two constituent polypeptides consists of two thrombopoietin receptor-binding domains linked to a human IgG-1 Fc fragment. It is expressed in E. coli. Approved by the FDA in August 2008, Nplate is indicated for the treatment of thrombocytopenia (low platelet count and hence impaired blood clotting ability) in patients with chronic idiopathic thrombocytopenic purpura (ITP) who display insufficient response to the alternative potential treatments of corticosteroids, immunoglobulins, or splenectomy. ITP is an autoimmune condition characterized by the destruction of platelets (thrombocytes) and megakaryocytes (the platelet-producing cells).

Thrombopoietin (TPO) is the primary physiological (stimulatory) regulator of platelet production. Nplate, by its thrombopoietin receptor-binding domains, binds to and activates TPO cell surface receptors in a manner analogous to endogenous TPO. The resultant increase in platelet production counterbalances platelet destruction by the immune system. Nplate's IgG Fc component serves to increase the product's serum half-life, facilitating its once weekly subcutaneous administration.

Safety and efficacy were largely assessed by two double-blind, placebo-controlled clinical studies and one open-label extension study involving 124 patients with chronic ITP. A clear overall increase in platelet production was observed in response to Nplate administration. The most common adverse effects noted included joint, stomach and shoulder pain, dizziness, and insomnia. However, several more serious effects were also reported, including a risk of bone marrow fibrosis and worsened thrombocytopenia after cessation of therapy.

Nplate is manufactured and distributed by Amgen (Thousand Oaks, CA). Subsequent to post-fermentation recovery and chromatographic purification, mannitol, sucrose, histidine, and polysorbate are added as excipients, and the final product is lyophilized.

Recothrom (thrombin, topical, recombinant) is a recombinant version of human thrombin produced in an engineered CHO cell line. It was approved by the FDA for controlling minor bleeding during surgery. The product is applied topically, directly on the surface of the bleeding or oozing tissue only. Thrombin (activated blood coagulation factor II, i.e., factor IIa) is a serine protease that functions at the terminal stage of the normal blood-clotting process. Its inactive circulating xymogen (prothrombin, i.e., factor II) is a 582 amino acid, 72.5 kDa glycoprotein containing six γ-carboxyglutamate residues toward its N-terminal end. It is proteolytically activated during the blood coagulation cascade by factor Xa and the active thrombin molecule consists of two polypeptides linked by a single disulfide linkage. The smaller polypeptide contains 49 amino acids while the larger contains 259 amino acids. [Physiologically thrombin then proteolytically activates fibrinogen (blood factor I), yielding fibrin, which forms the structural basis of a blood clot]. The recombinant thrombin displays an identical amino acid sequence to that of the native molecule.

The primary clinical evaluation undertaken was a multisite, randomized, double-blind study involving 411 surgical patients, who were treated with either recothrom or bovine thrombin. Efficacy was evaluated by the incidence of hemostasis 10 minutes post-product application, and no difference in efficacy between both treatment groups was recorded (95.4% versus 95.1%). The recombinant product, however, has a much reduced likelihood of triggering an immune response and the risk of accidental transmission of blood-bourne pathogens is also minimized. The most common side effect noted was complications at the incision site.

The recombinant molecule is synthesized and released from the producing CHO cell line in zymogen form. Downstream processing steps include its proteolytic activation, multiple chromatographic purification steps, and a solvent-detergent treatment step, as well as nanofiltration as viral clearance steps. No additives of human or animal origin are used in the manufacturing process. Histidine, mannitol, sucrose, sodium, and calcium chloride, as well as polyethylene glycol are added as excipients and the final product is lyophilized.

Gary Walsh, PhD, is an associate professor in the Industrial Biochemistry Program at the University of Limerick, Ireland. He is also a member of BioPharm International's editorial advisory board, 353.61.202664, Gary.walsh@ul.ie

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