New Biopharmaceuticals

A review of new biologic drug approvals over the years, featuring highlights from 2010 and 2011.
Jun 01, 2012


Table I
Cumulatively, the years 2010 and 2011 witnessed the approval of 19 biopharmaceutical marketing applications by FDA in the United States and EMA in the European Union combined (see Table I). 2010 was the better of the two years, with 13 total approvals. While neither year compares favorably to 2009, during which 20 such products were approved, these approval numbers are in line with average approval rates reported during the past several years (1–4). Products approved within the 2-year period included 9 antibodies, 4 fusion proteins, and 3 enzymes, as well as an enzyme inhibitor, a hormone, and a colony stimulating factor. Cancer and cancer-related conditions represented the principle indication (6 products), while the remaining products target a wide variety of conditions.

In terms of expression systems used, 14 of the 19 newly approved products are produced using mammalian (mainly Chinese hamster ovary, CHO) cell lines, two are expressed in Escherichia coli, while Saccharomyces cerevisiae, an insect cell-based expression system and a transgenic system is used to produce one product in each case. In overall terms, these figures reflect the ongoing dominance of mammalian-based expression systems in biopharmaceutical manufacture.

Digging a little deeper reveals that only 11 of the 19 therapeutic proteins were genuinely new biomolecular entities approved for the first time within the indicated timeframe. Three of the products (Actemra/RoActemra, Arzerra, and Victoza used to treat rheumatoid arthritis, chronic lymphocytic leukemia, and type 2 diabetes, respectively), although newly approved in one region over the past 2 years, had gained approval prior to 2010 in the other region (see Table I). Also approved, Nivestim is a biosimilar product used to treat neutropenia; while Prolia, used to treat osteoporisis, and Xgeva, used to treat bone loss associated with cancer, are effectively the same product with different indications. Lumizyme replaces the previously approved Myozyme, used to treat Pompe disease, while Scintimun, although gaining EU-wide centralized marketing authorization in 2010, had gained marketing authorizations in selected EU countries (the Czech Republic, Hungary, and Sweden) as far back as 1994.

ANTIBODY PRODUCTS

Of the nine antibodies that made it to market, one is chimaeric, one is humanized, and six are fully human. The period also witnessed the approval of a first generation murine antibody produced by traditional hybridoma technology (Scintimun). Such first generation monoclonal antibody (mAb) products are more characteristic of the 1980s and early 1990s than they are of this or indeed the past decade. Engineered antibodies (chimaeric/humanized/fully human) have predominated since that time due to the characteristic clinical disadvantages exhibited by fully murine products (e.g., immunogenicity, the inability to trigger effector functions in humans, and rapid removal from circulation). Given its in vivo diagnostic role (which does not rely upon triggering effector functions) and that it is radiolabeled, such characteristics are less significant in the context of the product in question.

Adcetris is notable in that it is a (CD30-directed) antibody-drug conjugate (used to treat Hodgkin's lymphoma). The conjugated toxin is monomethyl auristatin E (MMAE), an anticancer agent. On average, four molecules of MMAE are attached to each antibody molecule. Binding of the antibody conjugate to CD30-expressing cells is followed by endocytotic internalization and subsequent release of MMAE via proteolytic cleavage. MMAE is a microtubule disrupting agent. Binding to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and death by apoptosis.