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.
May 01, 2005


Gary Walsh, Ph.D.
Currently, some 160 biopharmaceuticals (defined as recombinant therapeutic proteins, monoclonal antibody-based products used for therapeutic or in vivo diagnostic purposes, as well as nucleic acid-based products) have gained marketing approval in the US and EU. Approx-imately one-fourth of new drugs coming on the market are biopharmaceuticals.1 These drugs have benefited some 325 million people worldwide2 and generate in excess of $30 billion annually, with sales projected to surpass $50 billion by 2010.3 Twelve biopharmaceuticals gained approval within the US and EU in 2004 (Table 1). Six are antibody-based products and two are engineered insulins. The other four are a blood factor, a vaccine containing a recombinant component, a growth factor, and a nucleic acid-based product.

The approvals profile mirrors several trends noted within the sector over the past few years. Antibody-based products continue to represent the single largest category of biopharmaceutical, with a total of 31 now having gained marketing approval. The global market for therapeutic antibodies was estimated at $5.4 billion in 2002 and is projected to reach about $17 billion by the end of the decade.4 The trend towards approval of engineered products also continues. Four of the six approved antibodies were engineered (one chimeric and three humanized) as were both insulin-based approvals. The insulin analog Levemir is particularly noteworthy. Its major engineered feature is the attachment of a fatty acid moiety to its amino acid backbone. Several older products have undergone such posttranslational engineering (e.g. pegylated interferons and products such as Cerezyme, which display altered glycocomponents), but Levemir is the first biopharmaceutical engineered by the attachment of a lipid group.




Cancer remains the primary indication (three products), again mirroring recent approval trends. Zevalin seeks to treat non-Hodgkin's lymphoma and Erbitux and Avastin treat colorectal cancer, which is the third most commonly diagnosed cancer worldwide (some 950,000 new cases annually). It is particularly prevalent in western countries.

Only eight approvals represent genuinely new molecular entities. Raptiva, Dukoral, and Zevalin added approval in a new region to an existing approval elsewhere. The recombinant blood factor-VIII product Advate is a modification of the already approved Recombinate.

In terms of expression systems used to produce the approved biopharmaceuticals, seven of the biologically produced products are expressed in Chinese hamster ovary (CHO) or other mammalian cell lines, again confirming the dominance of these cell types in biopharmaceutical production. Two others are produced using Escherichia coli. Tysabri has gained the most attention of all products approved in 2004, for all the wrong reasons. It was on the market for less than four months when sales (and use in ongoing clinical trials) were halted for safety reasons.

Macugen may start a new trend in that it is the first aptamer approved for therapeutic use. Aptamers (also termed decoys) are relatively short nucleic acid-based sequences that adopt a three-dimensional structure capable of binding to, and thereby inhibiting, a specific target molecule. Reference 5 is an excellent review of the topic.


Table 1. Biopharmaceuticals Approved in the US or EU or both in 2004.
APPROVED PRODUCTS The remainder of this article focuses upon the 12 approvals in 2004, with product information detailed in monograph format. Information was drawn from regulatory sources6,7 as well as the homepages of sponsoring companies (Table 1).

Advate Advate (octocog alfa) is a recombinant form of human blood factor-VIII produced in an engineered CHO-cell line. Its amino acid sequence is identical to that of the native factor-VIII. The product is quite heavily glycosylated, with 25 potential N-linked glycosylation sites and 12 O-linked glycans.

The European Commission approved Advate in March 2004. Advate is indicated for the treatment and prophylaxis of bleeding in patients with hemophilia A. The marketing authorization holder is Baxter AG. It is not a new molecular entity but a modification of the licensed factor-VIII product Recombinate (available in the US since 1992).