Biopharmaceuticals: Approval Trends in 2005 - - BioPharm International


Biopharmaceuticals: Approval Trends in 2005

BioPharm International
Volume 19, Issue 8

Naglazyme, which holds orphan status, was approved in the US in 2005 (and subsequently in Europe this year) for the treatment of patients with the lysosomal storage disease, mucopolysaccharidosis VI (MPS). This rare genetic defect, with an estimated 1100 cases in the developed world, is characterized by the absence of lysosomal N-acetylgalactosamine 4-sulfatase. The enzyme normally participates in the degradation of the glycosaminoglycan dermatan sulphate (a sugar polymer), and in affected individuals it accumulates in the lysosomes. Accumulation ultimately causes multiple medical complications, including skeletal deformity, joint disease, and cardiopulmonary disease. Until the approval of Naglazyme, there had been no satisfactory treatment available for MPS. Naglazyme therapy is essentially an enzyme replacement therapy. Cellular and, subsequently, lysosomal entry from the blood are likely mediated by the binding of the enzyme's bisphosphorylated oligomannose, oligosaccharide side chains, to cell- surface, mannose-6-phosphate receptors. This triggers endocytotic uptake. The product is provided as a concentrated solution (1 mg/mL enzyme) administered by infusion once a week. Immediately before use, the product is diluted with saline to 250 mL, which is infused over a four-hour period.

Product manufacture entails initial cell culture of the CHO producer strain with subsequent purification from the extracellular culture media. Initial harvest involves filtration, followed by an ultrafiltration-based concentration step. Purification is based on three, high-resolution chromatographic steps. Specific filtration, as well as incubation at low pH steps, are undertaken to inactivate any virus potentially present. Phosphate buffer constituents and polysorbate 80 are added as excipients.

Clinical efficacy was assessed in three studies, in which a total of 56 MPS patients were enrolled. Primary endpoints measured were based on physical endurance tests. Product administration resulted in improved 12-minute walk distance and three-minute stairs climbing tests. Administration also resulted in decreased urinary glycosaminoglycan (GAG) levels. The most common serious adverse events noted were infusion related. Additional adverse events included headache, fever, and upper respiratory tract infections. Virtually all patients administered Naglazyme develop antibodies against the product within the first few weeks of treatment, although the long- term significance of this, if any, remains to be determined. Naglazyme is manufactured and distributed by BioMarin Pharmaceuticals (Novato, CA).

Xolair (omalizumab) is an engineered (humanized) IgG antibody that specifically binds to human immunoglobulin E (IgE). The 149 kDa, glycosylated antibody is produced by an engineered CHO cell line. The product was approved in the EU in 2005, although it has been available in the US since 2003. It is indicated as an add-on treatment for asthma in individuals 12 years and older.

Allergic asthma is a chronic condition of the respiratory tract, usually treated with inhaled corticosteroids and beta agonists. The condition is underpinned by over expression of IgE in response to environmental allergens, such as pollen or dust mites. Allergen-specific IgE in turn binds to high affinity (FcεR1) receptors on airway-associated effector cells, including mast cells and basophils. Binding triggers release of histamine, prostaglandins, leukotrienes and cytokine-based proinflammatory mediators, thereby triggering a characteristic asthma attack.

Xolair brings about its intended effect by binding to the IgE, thereby inhibiting their interaction with the FcεR1 receptors. Dosage regimes typically entail subtaneous administration of 15–375 mg product every two to four weeks. The product is absorbed slowly from the site of injection, reaching peak serum concentrations after seven or eight days.

The product is manufactured via initial cell culture in batch fed suspension mode. Purification is achieved using a combination of protein A affinity chromatography, followed by both cation exchange and anion exchange chromatographic steps. Chromatography is followed by product concentration (ultrafiltration) and diafiltration. Sucrose, histidine, and polysorbate 20 are used as excipients and the final filter-sterilized product is lyophilized in single-use vials containing either 75 or 150 mg active ingredient.

Clinical safety and efficacy were determined mainly by five double-blind, placebo-controlled studies involving over 2,000 patients. In most trials, the number of asthma exacerbations per patient was significantly reduced by Xolair treatment. Exacerbations were defined as a worsening of asthma requiring either systemic corticosteroid administration, or a doubling of inhaled corticosteroid treatment levels. The most serious adverse reactions recorded were anaphylaxis and an increased malignancy rate (from 0.2 to 0.5% of patients). Additional adverse reactions included injection site reactions, headache, and an increased incidence of viral infection. Xolair is manufactured by Genentech (South San Francisco, CA) and is marketed by Genentech and Novartis (East Hanover, NJ).

Gary Walsh, PhD, senior lecturer, industrial biochemistry program, University of Limerick, Limerick City, Ireland, Tel. 353. 61. 202664, Fax 353.61.202568

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