Biopharmaceuticals: Approvals and Approval Trends in 2004 - Twelve biopharmaceuticals gained marketing approval in the US and EU in 2004. Antibody-based products represented the single largest product


Biopharmaceuticals: Approvals and Approval Trends in 2004
Twelve biopharmaceuticals gained marketing approval in the US and EU in 2004. Antibody-based products represented the single largest product category.

BioPharm International
Volume 18, Issue 5

Clinical trials clearly illustrate the effectiveness of NeutroSpec in confirming appendicitis in suspected cases. Hypersensitivity reactions represent a serious potential product side effect. Side effects noted during trials included hypotension, worsening of sepsis, flushing, and dyspena.

Macugen (pegaptanib sodium injection) is a synthetic pegylated oligonucleotide aptamer that specifically binds vascular endothelial growth factor (VEGF). It is indicated for the treatment of age-related neovascular ("wet") macular degeneration, which results from the proliferation of abnormal blood vessels in the eye, leading to retinal damage and vision loss. The process of vascularization (angiogenesis) is fueled by VEGF. Macugen adopts a three-dimensional shape that allows it to interact specifically with VEGF, thereby inhibiting its activity (note that the monoclonal antibody-based product Avastin achieves a similar effect in the context of cancer).

FDA approved it in December, 2004. It is manufactured by Gilead Sciences for Eyetech Pharmaceuticals and Pfizer.

The RNA-based oligonucleotide consists of 28 nucleotides of pre-defined sequence, chemically modified to render the product resistant to nuclease degradation. Two 20-kDa polyethylene glycol (PEG) molecules are covalently attached at one end of the nucleotide (to increase in vivo half life), yielding an overall product molecular mass of some 50 kDa. Final product is presented as a sterile, WFI-based solution containing sodium chloride as well as sodium phosphate as excipients. The product is administered by direct intravitreous injection.

Clinical assessment centered upon two studies involving almost 1,200 wet AMD patients. While both control and product groups continued to experience vision loss, the rate of vision decline experienced by Macugen-treated patients was significantly slower than in the case of control patients. The most frequent potentially serious side effects noted included endophthalmitis, retinal detachment, eye inflammation, irritation, and blurred vision.

Tysabri (natalizumab) is a recombinant, humanized IgG-based monoclonal antibody produced in engineered murine myeloma cells. It is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Subsequent to its biosynthesis and purification, Tysabri is formulated as a concentrate (20 mg/mL), indicated for once monthly IV infusion.

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 (comprised of endothelial cells lining brain capillaries), and hence preventing them from damaging the neuronal tissue.

The product is manufactured by Biogen Inc. and distributed by Elan. Initially approved by FDA in November, 2004, marketing and its use in ongoing clinical trials were halted in February 2005. The product received accelerated approval as it appeared to provide a substantial benefit to MS sufferers. One clinical trial recorded a reduction in the frequency of relapses by two-thirds (relative to placebo). A second trial (in which patients also received the interferon-based product Avonex, but for which Avonex did not prevent relapses) was also undertaken. Tysabri reduced the frequency of relapse by 50 percent in these cases.

FDA evaluation was based upon results from trials ongoing for one year. At that stage the most serious adverse events noted were infections and temporary hypersensitivity reactions. Approval was contingent upon continuing the trials for a second year. This data initially revealed one fatal and one additional case of multifocal leukoencephalopathy (PML). Both patients had received Tysabri in conjunction with Avonex for two years. The product remains withdrawn for all clinical use until ongoing investigations are completed.

Gary Walsh, Ph.D., is senior lecturer in the Industrial Biochemistry Program of University of Limerick, Limerick City, Ireland, 353.61.202.664, fax 353.61.202.568,

REFERENCES 1 Walsh G. Biopharmaceutical benchmarks 2003. Nature biotechnol. 2003; 21:865-870.

2 Biotechnology Industry Organization. Milestones 2004 Report. Available at

3 Pavlou AK, Reichert JM. Recombinant protein therapeutics - success rates, market trends and values to 2010. Nature biotechnol. 2004; 22:1513-1519.

4 Reichert JM, Pavlou A, Monoclonal antibodies market. Nat. Rev. Drug Discovery 2004; 3: 383-384.

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