Biopharmecuticals: Approval Trends in 2006

September 1, 2007
Gary Walsh, PhD

Associate Professor in the Industrial Biochemistry Program at the University of Limerick. He is also a member of BioPharm International's Editorial Advisory Board.

BioPharm International, BioPharm International-09-01-2007, Volume 20, Issue 9

There were notable approvals in nonparenteral delivery systems and biosimiliars in 2006.

The year 2006 witnessed the approval of 13 biopharmaceuticals in the United States or European Union (Table 1) including four hormones, three antibody-based products, three therapeutic enzymes, one recombinant vaccine, an anticlotting agent, and a nucleic acid–based product. Major target indications included hereditary genetic conditions (four products, three of which—Elaprase, Naglazyme, and Myozyme—have orphan status), growth deficiency (two products), and neovascular macular degeneration (two products).

Table 1. Biopharmaceuticals (recombinant proteins and monoclonal antibody-based products) approved in the US or EU in 2006

Only 10 of the 13 products were genuinely new to the market. Naglazyme, Tysabri, and Macugen, although approved in one region last year, had gained approval before 2006 in some other world region.

In terms of expression systems used, five of the approved biopharmaceuticals are produced in mammalian cell lines, four in Escherichia coli, and two in Saccharomyces cerevisiae, again confirming the prominence of these three expression systems in the biopharmaceutical sector. One product (Macugen) is produced by solid-phase organic synthesis. Another (Atryn) is particularly noteworthy because it is the first biopharmaceutical produced in a transgenic animal to gain regulatory approval.

Gary Walsh, PhD

Like 2005, last year also witnessed notable approvals in the context of nonparenteral delivery systems and biosimiliars. The approval of Exubera (a recombinant insulin) marks a watershed for pulmonary-based biopharmaceutical delivery. The biosimiliar product Omnitrope (recombinant human growth hormone), approved in 2005 by the Australian authorities, gained approval in both Europe and the US in 2006. And the EU further underlined its acceptance of the principle of biosimilarity by approving a second product (Valtropin, also a recombinant human growth hormone) last year.

The remainder of this article focuses on individual products approved in 2006, with product information detailed in a monograph format. Information was drawn from regulatory sources1–3 and the Internet homepages of sponsoring companies. Because monographs detailing Naglazyme and Macugen were included in previous articles4,5 they are not considered below. Although Tysabri also has been covered before4 , a revised monograph is included here because of the altered indications and restrictions linked to its resumed approval last year.

PRODUCTS APPROVED

Atryn (antithrombin alfa) is a recombinant form of human antithrombin (AT) produced by transgenic goats in their milk. The 432 amino acid single-chain protein is, like the native human molecule, glycosylated. It harbors four N-linked glycosylation sites (Asn 96, 135, 155, and 192) and three disulfide linkages. The recombinant molecule displays significant differences in its glycosylation profile compared with native human AT, both in terms of monosaccharide composition (for example, it is fucosylated and less sialylated) and overall side chain structure. This influences the pharmacokinetics and heparin binding affinity of the product.

Quick Recap

The European Commission approved Atryn under exceptional circumstances in July 2006 because the rarity of the condition prevented generation of comprehensive clinical data. The product is an anticlotting agent and is indicated for the prophylaxis of venous thromboembolism in surgery of patients with congenital antithrombin deficiency. The original marketing authorization holder was Genzyme Europe, but this has since been transferred to Leo Pharma (Ballerup, Denmark).

Native AT is a plasma glycoprotein that is synthesized and stored in the vascular endothelium and normally present in blood at levels of 125 µg/mL. It is one of the most significant natural inhibitors of blood coagulation and brings about its anticlotting effect by complexing with, and hence directly inhibiting, several blood clotting factors, most notably thrombin (factor IIa) and factor Xa. The complex is then rapidly cleared from circulation via internalization and degradation in liver cells. In addition to a coagulation factor binding domain, AT displays a heparin binding domain; binding of heparin greatly accelerates the rate of complex formation. Heparin is normally co-administered with the product.

Hereditary AT deficiency can be categorized by a decrease in absolute serum AT levels or by the presence of mutated (dysfunctional) forms. The major clinical consequence is an increase in the risk of clot formation in deep veins, pulmonary embolism, and venous clot formation at uncommon sites (e.g., hepatic, retinal, or cerebral venous thromboembolic events). Particularly high-risk circumstances include surgery, bed rest, and pregnancy.

The manufacture of Atryn involves initial harvest (i.e., milking the animals), followed by clarification and purification via multiple chromatographic steps, which include specific heparin affinity, hydrophobic interaction, and ion exchange steps. A nanofiltration step is used as a precautionary viral removal step and glycine, sodium chloride, and sodium citrate are added as excipients. After filling into vials, the product is lyophilized.

Product administration entails infusion after reconstitution with water for injection (WFI). Limited clinical trial results have been reported, mainly involving patients with hereditary AT deficiency in high-risk situations (surgery and pregnancy), with incidence of deep vein thrombosis. Common side effects include haemorrhage, headache, and nausea. Atryn's active ingredient is sourced from transgenic animals maintained by GTC biotherapeutics (Framingham, MA). Leo Pharma (Ballerup, Denmark) markets the product in Europe.

Elaprase (idursulfase) is a recombinant form of the human lysosomal enzyme iduronate-2-sulfatase, produced in an engineered transformed human cell line (HT-1080). The 525 amino acid enzyme displays a molecular weight of 76 kDa and harbors two disulfide bonds, eight N-linked glycosylation sites, and a formylglycine residue at position 59 that is necessary for biological activity. Elaprase, which is an orphan product, gained approval in the US in 2006 (and subsequently in the EU in January 2007). It is indicated for the long-term treatment of patients with Hunter syndrome (mucopolysaccharidosis II, MPS II). MPS II is a rare, X-linked recessive genetic lysosomal storage disease caused by a lack of functional lysosomal iduronate-2-sulfatase. This enzyme functions naturally in the body to cleave sulphate groups from two glycosaminoglycans (GAGs)—dermatan sulphate and heparin sulphate. GAGs are unbranched polysaccharides consisting of various uronic acids and hexosamine residues, which largely play structure-related roles in the extracellular space, particularly those associated with connective tissue. Lack of the enzyme results in GAG accumulation in most organs and tissues, resulting in organ or tissue dysfunction. Clinical manifestations usually become apparent within the first 12–36 months of life and are progressive, severe, and life threatening.

Elaprase is manufactured through the initial culture of the human producer cell line, chosen for production due to its ability to attach complex, high mannose-type oligosaccharide side chains to the enzyme's polypeptide backbone. Specifically, the presence of mannose-6-phosphate (M6P) facilitates product binding to cell surface-M6P receptors, with subsequent cellular internalization and delivery to lysosomes—the exact target organelle.

Product purification incorporates six chromatographic steps as well as two ultrafiltration and one viral filtration step. Formulation entails the addition of sodium chloride (to provide an isotonic solution for subsequent administration), sodium phosphate (a buffering agent) and polysorbate 20 (as a stabilizing agent and for protection against agitation-induced aggregation). The final product is filter sterilized and aseptically filled into presterile vials. Each vial contains 3 mL of a 2 mg/mL active ingredient solution. The recommended dosage regimen is once weekly intravenous infusion (after product dilution to 100 mL in saline) over a time course of 1–3 hours.

Product safety and efficacy were established by a randomized, double blind, placebo-controlled trial containing 96 MPS II patients. Primary efficacy indications used were distance walked during a six-minute walk test and pulmonary function. The most common adverse events were infusion-related, including life-threatening anaphylactoid reactions. Elaprase is manufactured and marketed by Shire Human Genetic Therapies, Inc. (Danderyd, Sweden).

Exubera (insulin, human recombinant) is identical in amino acid sequence to native human insulin. It is produced by recombinant means in an engineered E. coli K 12 strain, and gained approval for general medical use in 2006 both in the EU and US. Unlike formerly approved insulins, which are administered parenterally, Exubera is administered via the pulmonary route using a specially designed inhaler. It is indicated for the treatment of adults with diabetes mellitus, for the control of hyperglycemia. The inhaled insulin is absorbed more quickly than subcutaneously administered regular human insulin and has an onset of action that is similar to subcutaneously administered rapid-acting engineered insulin analogues, such as insulin lispro.

After its absorption from the lung into the blood Exubera promotes a decrease in blood, glucose levels (and its other characteristic effects) in the normal manner, via interaction with the insulin receptor.

The manufacture of Exubera consists of 16 steps. After initial fermentation, the E. coli cells are harvested via centrifugation, with subsequent cell disruption and recovery of the insulin-containing fusion pro-product. Downstream processing includes a concentration step, a step to release free insulin from the pro-product and multiple chromatographic purification steps. Excipients then added include mannitol (a stabilizing and bulking agent) as well as glycine and sodium citrate (buffering and stabilizing agents). The product is spray dried, allowing its subsequent storage at room temperature. Product particles display a mean particle diameter of approximately 3 µm, which facilitates aerosol delivery to the deep lung. The finished product is filled into unit dose blisters containing 1 mg or 3 mg of active substance. These fit a manually operated, reusable inhaler device.

Exubera has a duration of action comparable to subcutaneously injected regular human insulin and longer than rapid-acting insulin. It is administered immediately before food consumption and in regimens that include a longer acting insulin. When administered to healthy volunteers, the onset of (glucose lowering) activity was observed within 10 minutes with maximum effect noted after two hours and a total duration of about six hours.

Clinical studies underpinning safety and efficacy were conducted using 2,500 adult patients with type 1 or type 2 diabetes, and the primary efficacy parameter monitored was invariably glycemic control. Like other insulin preparations, hypoglycemia represented the most commonly reported adverse event. Product administration was also found to cause a greater decline in lung function than controls and, as a consequence, the product is contraindicated in patients who smoke or who have poorly controlled or unstable lung disease. Exubera is distributed by Pfizer (New York City, NY) and licensed from Nektar (San Carlos, CA).

Gardasil (human papillomavirus vaccine, types 6,11,16,18, recombinant), also marketed as Silgard in the EU, is a multivalent vaccine preparation containing the purified recombinant major surface capsid (L1) protein of human papillomavirus (HPV) types 6,11,16, and 18, produced separately in engineered strains of S. cerevisiae. The product gained approval in 2006 in both the US and EU and is used to vaccinate girls and women (9–26 years of age) against cervical and vaginal cancer and genital warts caused by the HPV types listed. HPV infection represents the most common sexually transmitted disease worldwide, with some 50% of young women being infected within five years of becoming sexually active. Native papillomavirions are approximately 60 nm in diameter. These double-stranded DNA viruses display an icosahedral symmetry made by 72 pentamers of the L1 caspid protein. Some 40 different HPV strains preferentially infect the genitals and 13 of these are highly carcinogenic. They are believed to be the primary cause of cervical cancer, which is the second most common type of cancer causing deaths in women worldwide. Types 6,11,16, and 18 are the most commonly occurring HPVs and these are believed to cause the vast majority of cancers and genital wart growth.

Gardasil manufacture requires separate fermentation of four engineered S. cerevisiae strains, each housing the gene coding for the P1 capsid protein of one of the HPV strains listed. Following fermentation, the cells are recovered by microfiltration and the recombinant protein is released via homogenization. In each case, the recombinant capsid proteins spontaneously self-assemble into large virus-like particles (VLPs), rendering their subsequent purification— via size-based membrane filtration, ultrafiltration, and chromatography—relatively straightforward. The purified antigen (VLP) is then absorbed onto amorphous aluminium hydroxyphosphate sulphate, which acts as an adjuvant. Also added are sodium chloride, histidine, polysorbate 80, and sodium borate buffer as excipients. The product is presented as single use, 0.5 mL-doses in either vials or prefilled syringes with each dose containing 20 µg of type 6 L1 protein and 40 µg of each of the other L1 proteins. The administration schedule usually entails intramuscular injection of an initial dose, with subsequent doses delivered at months two and six.

Clinical trials assessing product safety and efficacy involved more than 20,000 females and clearly showed a protective effect. The most common side effects noted were pyrexia (fever) and reaction site injections. Gardasil is manufactured (and distributed in the US) by Merck (Whitehouse Station, NJ) and is marketed in the EU by Sanofi Pasteur (Lyon, France). It is also marketed in the EU as Silgard by Merck Sharp & Dohme (Hertfordshire, UK).

Lucentis (ranibizumab) is a 48 kDa humanized MAb antigen-binding fragment (Fab fragment) consisting of a 214 amino acid light- chain fragment linked by an interchain disulfide bond to a 231 amino acid heavy-chain fragment. Produced in E. coli, the fragment binds vascular endothelial growth factor A (VEGF-A) with high affinity. It was first approved in the US in 2006, and subsequently in the EU (in January 2007). It is indicated for the treatment of neovascular (wet) age-related macular degeneration (wet AMD), a condition characterized by the formation of abnormal, leaky blood vessels under the macula (the central part of the retina). This condition can result in the lifting of the retina and hemorrhage in the subretinal space. As a progressive, degenerative disease, central vision is gradually blurred and the condition is most common in persons aged 75 years and older.

VEGF-A, via binding to its endothelial cell surface receptors, is believed to be a major driving force for abnormal blood vessel formation. Binding of Lucentis to VEGF-A prevents interaction with the receptor, thereby reducing abnormal blood vessel growth.

The manufacturing process of Lucentis involves initial fermentation of the E. coli producer cell which carries cDNAs encoding variable light and variable heavy antibody chains fused to human constant light and constant heavy (CH1) domains. The light and heavy chains fold into their native conformation after their secretion into the periplasm. Soluble product is fully released from the E. coli via initial homogenization and a subsequent heating step that precipitates cellular debris. High-resolution purification is achieved by a combination of four subsequent chromatographic steps, followed by the addition of trehalose, histidine, and polysorbate 20 as excipients.

Lucentis is administered by direct intravitreal injection (0.5 mg active in a final volume of 0.05 mL) once monthly, and usually for an initial period of 3 months, with subsequent administration being dependent upon results from routine visual monitoring.

The clinical efficacy and safety of Lucentis was assessed primarily in three randomized, double blind studies over a period of 24 months using a total of 1,323 patients (879 of which received Lucentis, with 444 untreated controls). The primary efficacy endpoint was either the proportion of patients who maintained vision (defined as losing fewer than 15 letters of visual acuity) compared with baseline or the mean change in visual acuity. The studies showed that Lucentis administration resulted in an increase in mean change in visual acuity as compared with continuous deterioration in the case of controls. The most common adverse reactions noted were conjunctival hemorrhage, eye pain, vitreous floaters, increased ocular pressure, and inflammation. Lucentis is manufactured by Genentech (San Francisco, CA) and is marketed in Europe by Novartis Europharm (Sussex, UK).

Myozyme (alglucosidase alfa) is a recombinant form of the human lysosomal enzyme acid α-glucosidase (GAA). The 109 kDa glycoprotein is produced in an engineered CHO cell line. It has designated orphan status in both the US and EU and was approved in both regions in 2006. Myozyme is indicated for the treatment of Pompe disease, a rare genetic condition characterized by a deficiency of lysosomal GAA activity. The condition is also known as glycogen storage disease type II, glycogenosis type II, or acid maltase deficiency. GAA functions to degrade lysosomal glycogen via the hydrolysis of both the α-1-4 and α-1-6 glycosidic bonds characteristic of the molecule. Pompe disease is characterized by accumulation of lysosomal glycogen stores in various cell and tissue types, particularly cardiac, skeletal, and respiratory muscle cells, leading to dysfunction of the effected cell types.

The clinical presentation of the condition, which presumably is dependent on residual levels of catalytically active enzyme produced, ranges from a severe, rapidly fatal infant-onset form to a more slowly progressing late onset (juvenile or adult) form.

Myozyme manufacture includes cell culture, product recovery, chromatographic purification, and formulation. It is presented in lyophilized form in glass vials containing 50 mg active, as well as mannitol, polysorbate 80, and sodium phosphate as excipients. The recommended dosage regimen entails intravenous infusion, once every two weeks over approximately four hours, at a typical dosage level of 20 mg/kg body weight.

Product administration is followed by cellular uptake, likely through initial binding to cell surface mannose-6-phosphate receptors, with subsequent lysosomal delivery. Safety and efficacy were established primarily by two clinical trials involving a total of 39 Pompe disease patients ranging in age (at first treatment) from 1 month to 3.5 years. All were administered product and results were compared with historical data of (matched) untreated infantile-onset Pompe disease patients. Primary efficacy indicators included the proportion of patients who died or needed invasive ventilator support due to respiratory muscle failure. Both parameters were substantially improved with myozyme therapy. For example, historical control data indicated a mortality rate of 98% by 18 months of age compared with about 11% for the treatment group. The most common adverse effect noted is hypersensitivity reactions, including life-threatening anaphylactic reactions. Myozyme is manufactured and marketed by Genzyme (Cambridge, MA).

Omnitrope (somatropin) is a recombinant form of human growth hormone (hGH) produced in an engineered E. coli. Like the native molecule, Omnitrope is an unglycosylated, 191 amino acid single-chain polypeptide with a molecular mass of 22.1 kDa. It first gained approval within the EU in (April) 2006 as a similar biological medicinal product (a biosimiliar) and was subsequently approved in the US later that year. It is indicated for the treatment of children and adults with growth failure due to inadequate endogenous hGH secretion or also (in the EU) growth failure associated with chronic renal insufficiency, Turner syndrome, or Prader-Willi syndrome.

Omnitrope binds the native hGH cell surface receptor, thereby triggering the characteristic direct and indirect growth-promoting and related effects of this hormone.

The manufacture of Omnitrope is initiated by fermentation, during which the product accumulates intracellularly. Fermentation is followed by cell harvest and lysis, product recovery, and chromatographic purification. Glycine and phosphate buffer components are added as excipients and the final product is lyophilized in glass vials. Omnitrope is intended for daily subcutaneous administration with exact dosage levels being adjusted for individual patients.

As a biosimiliar application the clinical evidence needed to support approval in the EU required demonstration of the product's similarity to a reference medicine (i.e., an hGH product already approved) in terms of quality, safety, and efficacy. The reference medicine chosen was Genotropin, an hGH product that first gained approval in Europe in 1988. Therefore, as required by EU biosimiliar legislation, the applicant was required to submit a full quality module and reduced clinical and nonclinical modules. Efficacy was demonstrated largely by a nine-month clinical study involving 89 children lacking hGH. Treatment with either Omnitrope or Genotropin yielded similar increases in height and speed of growth (equivalent to approximately 10.7 cm/year). This and a second trial involving 51 children who were administered product for a year also underpinned safety data. Side effects associated with Omnitrope (transient local skin reactions and in adults, mild edema, and muscle or joint pain) were also similar in type and severity to those associated with the reference medicine.

The active ingredient is manufactured by Sandoz (Kundl, Austria), which also markets the product in both the EU and US.

Preotact (parathyroid hormone) is a recombinant form of human parathyroid hormone produced in an engineered E. coli cell line. The 9.4 kDa, 84 amino acid hormone is identical in sequence to the native human molecule and is devoid of disulfide bonds or a glycocomponent. It gained approval in the EU in 2006 and is indicated for the treatment of osteoporosis in postmenopausal women at high risk of fractures.

Postmenopausal osteoporosis is characterized by low bone mass with resultant increase in bone fragility and hence increased risk of fracture. Parathyroid hormone functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high affinity cell surface receptors for the hormone. It also increases intestinal absorption of calcium.

The manufacture of Preotact involves initial (1100-L scale) fermentation of the producer E. coli (cell line PAL 1000). The cells contain an expression plasmid (pJT42) housing a synthetic gene coding for human PTH fused to a 21 amino acid E. coli outer membrane protein A signal peptide. As a result, the fusion product is secreted into the culture medium, with automatic removal of the leader sequence from the fusion product by an E. coli signal peptidase. Following fermentation, the cells are removed from the product stream by a combination of centrifugation and filtration, followed by an ultrafiltration or diafiltration step. Purification includes five chromatographic steps, with addition of mannitol, sodium chloride, and citric acid as excipients, followed by lyophilization. The final product is presented as a dual chamber cartridge, with the second chamber containing the reconstitution solvent (WFI, containing metacresol as a preservative). The recommended administration schedule entails once daily abdominal subcutaneous injection of 100 µg active ingredient.

The major clinical study underpinning product approval was an 18-month, double blind, placebo-controlled trial involving more than 2,500 post menopausal women. The trial demonstrated no significant difference in the incidence of non-vertebral clinical fractures, but demonstrated a 61% relative reduction of vertebral fracture (3.37% versus 1.32%) associated with product administration. Preotach treatment also increased the mineral density of the spine as well as hip bone. The most common side effects noted included increased serum and urine calcium levels (hypercalcemia and hypercalciuria) as well as nausea. The biologically active substance is manufactured by SynCo BioPartners (Amsterdam, the Netherlands) and it is marketed by Nycomed (Roskilde, Denmark).

Tysabri (natalizumab) is a recombinant, 149 kDa humanized IgG4 monoclonal antibody produced in engineered murine myeloma cells. In 2006 it was approved for resumed marketing in the US and approved for the first time in the EU. It is indicated as a monotherapy for the treatment of the relapsing forms of multiple sclerosis (MS) under certain conditions.

Initial accelerated approval had been granted by the FDA in November 2004 on the basis of the substantial benefit recorded to MS sufferers as revealed by initial trials. At that stage, the most serious adverse events noted were acceptable infections and hypersensitivity reactions, but approval was contingent upon continuing the trials for an additional year. Marketing and its use in ongoing clinical trials was subsequently halted in February 2005 when the studies revealed two cases of fatal progressive multifocal leukoencephalopathy (PML, a rare viral infection of the brain) in patients receiving Tysabri in conjunction with interferon therapy. The FDA allowed resumption of a clinical trial in February 2006 and the product subsequently gained approval under more limited conditions (e.g., it must be used as a monotherapy only, and it is made available under a restricted distribution program).

The manufacture of Tysabri entails initial culture of the producer cells in a 15,000-L bioreactor, using media devoid of serum or animal-derived components. Cells are then removed from the antibody-containing media by membrane filtration and the product is purified by a combination of protein A affinity, anion exchange, and hydrophobic interaction chromatography. Additional (viral clearance) steps undertaken during downstream processing include low pH treatment and nanofiltration. The final product is formulated in the presence of sodium chloride, polysorbate 80, and sodium phosphate buffer components as excipients and is presented as a 15 mL-concentrate (20 mg active/mL) in glass vials.

The recommended dosage regimen includes initial dilution of the concentrate in 100 mL saline, followed by once monthly administration via IV infusion over one hour.

Tysabri binds specifically to selected integrins found on the surface of most white blood cells (with the exception of neutrophils). These integrins serve as recognition docking markers, allowing binding to vascular endothelial cells, and thereby facilitating leukocyte migration across the endothelium. Tysabri administration blocks this interaction and increases the numbers of circulating leukocytes in the blood by inhibiting transmigration out of the vascular space.

While the exact underlining causes of multiple sclerosis remain to be elucidated, the condition is believed to be an autoimmune one, in which selected immune system cells (leukocytes) attack the central nervous system. Tysabri therefore may work by blocking migration of such leukocytes across the blood-brain barrier (comprising endothelial cells lining brain capillaries), and hence preventing them from damaging the neuronal tissue.

Two major clinical studies (each two years in duration) were undertaken, one using Tysabri as a monotherapy and the other involving its use in combination with interferon. Both showed clear benefit in the context of MS. In the monotherapy trial, for example, Tysabri treatment reduced the percentage of patients experiencing a sustained increase in disability from 29% to 17% and increased the number of patients remaining relapse free from 41% to 67%. The most common side effects noted in the studies included an increase in general infection rate, rash, headache, dizziness, fever, and fatigue. The increased risk of infections, particularly PML, means the product should not be administered to those already particularly prone to acquiring an infection (e.g., immunocompromised individuals), to those who have cancer or who are also receiving other long term MS drugs (interferon or glatiramer acetate), or who are under 18 years of age.

The product is manufactured by Biogen Idec (Cambridge, MA) and distributed by Elan in both the US and EU.

Valtropin (somatropin) is a recombinant form of human growth hormone (hGH) produced in S. cerevisiae. It is a nonglycosylated, single-chain 22 kDa, 191 amino acid polypeptide of identical sequence to that of native hGH. It gained approval in the EU in April 2006 and, like Omnitrope (see above), is classified as a biosimiliar medicinal product. Valtropin is indicated for the treatment of children with growth failure or reduced growth rates because of either inadequate secretion of endogenous growth hormone, Turner syndrome, or chronic renal insufficiency. It is also indicated for use in adults displaying growth hormone deficiency.

After initial fermentation of the producer yeast cells, the crude product is purified via multiple chromatographic steps. Glycine, mannitol, and sodium phosphate buffer constituents are added as excipients. The final product is then lyophilized, with each vial containing 5 mg (equivalent to 15 IU) of active ingredient. A prefilled syringe containing reconstituting solution (1.5 mL WFI containing 0.3% M cresol) is also supplied. The reconstituted product is for repeat use as a multidose product. Dosage is individualized for each patient and administration involves a daily subcutaneous injection.

The reference medicine chosen with which to compare Valtropin was Humatrope, a recombinant hGH available in the EU since 1990. The indications are the same for both medicines and trials showed them both to have similar safety and efficacy profiles. The main clinical study supporting approval entailed treatment of 149 children with either Valtropin or Humatrope over a 12-month period. Similar increases in height gain and speed of growth were recorded (11.4 and 10.5 cm/year, respectively) and the most common side effects noted for both were mild edema and transient local skin reactions.

The biologically active substance is manufactured by LG Life Sciences (Joenbuk-do, South Korea) and BioPartners (Russelsheim, Germany) holds the European marketing authorization.

Vectibix (panitumumab) is a 147 kDa human IgG 2 kappa monoclonal antibody produced by recombinant means in a CHO cell line. The product, which binds to the human epidermal growth factor receptor (EGFR), was approved in 2006 in the US and is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma.

The EGFR is a transmembrane glycosylated protein. It is constitutively expressed in many normal cell or tissue types, including those of the skin and hair follicle. Its overexpression is, however, linked to various cancers including colorectal cancer. Binding of receptor ligands (EGF and transforming growth factor-α) triggers signal transduction, which results in activation via phosphorylation of various intracellular protein tyrosine kinases. These, in turn, regulate transcription of various gene products that promote cell growth, proliferation, and transformation. Vectibix, by binding to the EGFR, competitively inhibits binding of native ligand to the receptor without itself triggering signal transduction. The growth of target cells is thereby inhibited and apoptosis is usually triggered.

The manufacturing process of Vectibix involves recovery subsequent to cell culture, followed by multiple chromatographic purification steps. Sodium chloride and sodium acetate are added as excipients and the final filter-sterilized product is formulated as a liquid intended for intravenous (IV) infusion, with the active ingredient present at a concentration of 20 mg/mL. Recommended dosage entails infusion of 6 mg active/kg over 60–90 minutes once every 14 days. The elimination half life of the product is approximately 7.5 days.

Clinical data supporting approval was predominantly generated by an open label, multinational randomized trial involving 463 patients. One group was administered the product while the other group received supportive care alone. Administration of Vectibix resulted in prolonged progression-free survival, from an average of 60 days to 96 days. The most common and sometimes severe negative side effects included dermatologic toxicities and adverse (sometimes severe infusion related) reactions also occurred in a minority of recipients. The product is manufactured and marketed by Amgen (Thousand Oaks, CA).

Gary Walsh, PhD, is an associate professor in the Industrial Biochemistry Program at the University of Limerick, Limerick City, Ireland, +353.61.202664, Gary.walsh@ul.ie

REFERENCES

1. US Food and Drug Administration. Approvals of FDA-regulated products. Available from www.fda.gov/opacom/7approvl.html.

2. European Medicines Agency. EMEA annual report 2006. Available from http://www.emea.europa.eu/index/indexh1.htm.

3. European Medicines Agency. EPARs for authorised medicinal products for human use. Available from http://www.emea.europa.eu/htms/human/epar/eparintro.htm.

4. Walsh G. Biopharmaceuticals: approvals and approval trends in 2004. BioPharm Int. 2005;18(8):58–65.

5. Walsh, G. Biopharmaceuticals: approval trends in 2005. BioPharm Int. 2006;19(8):58–68.