Nucleic-acid- and cell-based therapeutics - Pharmaceutical Biotechnology: Concepts and Aapplications - page 456

Box 14.4
Product case study: Macugen
Macugen (tradename) is the fi rst and thus far only aptamer approved for general medical use.
It was approved by the FDA in December 2004. The product is a synthetic PEGylated oligonu-
cleotide with binding specifi city for vascular endothelial growth factor (VEGF). It is indicated
for the treatment of neovascular ('wet') age-related macular degeneration (AMD).
The RNA-based aptamer consists of 28 nucleontides of predefi ned sequence, chemically
modifi ed in order to render it resistant to nuclease degradation. Two 20 kDa PEG molecules are
also covalently attached at one end of the nucleotide. The overall product molecular mass is 50
kDa. Final product is presented as a sterile solution containing sodium chloride and sodium
phosphate as excipients.
The target indication (age-related neovascular or 'wet' macular degeneration) results from
the proliferation of abnormal blood vessels in the eye, which leads to retinal damage and loss
of vision. The process of vascularization (angiogenesis) is driven by VEGF. Macugen adopts
a three-dimensional shape that allows it to interact specifi cally with VEGF, thereby inhibiting
its activity (the monoclonal antibody-based product Avastin, Chapter 13, achieves a similar
effect, but in the context of cancer). The product is administered directly to the site of action
by intravitreous injection. Absorption from the eye into the general bloodstream occurs only
very slowly, allowing a frequency of administration of once every 6 weeks. Subsequent product
metabolism is via nuclease degradation.
Initial clinical assessment involved some 1200 wet AMD patients. Although both control and
product groups continued to experience vision loss, the rate of vision decline experienced by
macugen-treated patients was signifi cantly slower than in the case of control patients. The most
frequent/potentially serious side effects noted during these trials were endophthalmitis, retinal
detachment, eye infl ammation/irritation and blurred vision, although rare cases of anaphylaxis
have also been reported. Macugen is marketed by Eyetech Pharmaceuticals and Pfi zer.
Transplantation entails the transfer of living cells/tissue/organs from a donor to a recipient. In
some cases (e.g. many skin grafting procedures) the donor and recipient are actually the same
individual, and this is termed autologous transplantation. More usually, however, the donor and
recipient are different individuals, and this is termed allogeneic transplantation.
Common forms of transplantation include whole blood transfusions (Box 14.5), bone marrow
transplantations, skin grafting and transplantation of a wide range of organs, including kidneys,
liver, pancreas, lungs and heart. Improvements in surgical transplant techniques, along with the
availability of effective immunosuppressive drugs (including some antibody-based drugs; Chapter
13), render 1-year success rates for most organ transplants in the 75-95 per cent range.
Tissue/organs destined for transplant are rarely considered to be pharmaceutical products. The
material for transplant is usually harvested directly by clinicians via surgical or other appropriate
techniques, followed by direct transplantation without signifi cant in vitro processing.
'Tissue- or cell-engineered' products represent a small but signifi cant subgroup of cell-based
products. Such products also consist of/contain fully differentiated cells but do undergo some