Biopharmaceuticals Approval Trends in 2013

In 2013, 19 products containing new biopharmaceutical molecular entities were approved in the United States and/or the European Union (see Table I). Approval numbers for 2013 are above average as compared to the previous five years, which recorded a mean approval rate of 13 products (1-4). This annual approval rate was surpassed only in 2009, a year in which 20 new products came on the market (see Figure 1).

Products approved last year included four monoclonal antibodies (mAbs), four hormones, three blood factors, as well as two each of subunit vaccines, colony stimulating factors (CSFs), fusion products, and enzymes. Five products are indicated against cancer, again rendering it the single most common target indication. A further three aim to treat various forms of haemophilia, while the remainder target a wide range of additional medical conditions.

In terms of expression systems used, a total of eight of the products approved are expressed in mammalian cell lines (seven in CHO cells, one in Sp20), six are produced in yeast-based systems, four in E. coli and one in an insect-based system. These approvals reflect trends in expression systems used over the past several years, with no novel expression systems making a debut in 2013.

Nineteen approvals, by any metric, is a healthy headline number. Digging a little deeper, however, reveals that just over two-thirds of these (a still credible 13 products) were genuinely new first time approvals. Six of the products, although newly approved in one region last year, had gained approval prior to that in the other region (Table I). Moreover, a significant difference in the absolute approval numbers was witnessed in the regions. A total of 16 approvals were recorded in Europe, while only five biopharmaceuticals came on the market in the US in that same period. This trend can partly be explained by Europe playing catch up in the case of some products; five of Europe’s 16 new approvals were already on the US market prior to 2013.

Overall, 2013 can be considered quite a successful year in terms of new product approvals. Several of those newly approved products underpin particularly noteworthy technical, medical, or regulatory milestones, and are thus the focus of the remainder of this article.

Table I: Biopharmaceuticals (recombinant proteins, monoclonal antibody or biosynthesized nucleic acid-based products) approved in the United States and/or European Union in 2013. Table courtesy of author.

Biosimilars
While the advent of approved biosimilar products remains a future prospect in the US, European regulators brought three such products to market in 2013. This brings the total number of biosimilars approved thus far in Europe to 19. This total, however, represents a comparatively more modest 10 genuinely different products, as several are marketed under two or more trade names, but with each possessing its own marketing authorization.

While Grastofil (Table I) joins a stable of several biosimilar filgrastims already on the market, the other two products represent first-in-class biosimilar approvals. Ovaleap (Teva Pharmaceuticals) is the first biosimilar follicle stimulating hormone (FSH) to be approved; it will compete with two FSH products already marketed in Europe (Merck-Serono’s Gonal-f and Organon’s Puregon).

Hospira’s Inflectra  (also approved under a separate marketing authorization as Remsima) is even more interesting in that it represents the first ever biosimilar mAb to gain approval in Europe. It is a biosimilar version of Remicade, which has been on the market in Europe since 1999 and is used to treat a wide range of inflammatory conditions. Remicade generated annual global revenues in the region of $7.5 billion in 2012.  

Engineered antibodies
Genentech’s Gazyva represents another milestone in antibody approvals, being the first glycoengineered mAb to come on the market in the US. mAbs are glycoproteins, carrying an oligosaccharide side chain attached to asparagine residue 297 of the antibody’s heavy chains.  This glycocomponent plays a central role in triggering antibody-dependant cellular cytoxicity (ADCC), which appears to be the principle mechanism by which antibodies trigger the destruction of cancer cells. This glycocomponent normally contains a fucose sugar residue and removal of the fucose enhances antibody ADCC activity by up to 100 fold. Gazyva’s glycocomponent is enriched in non-fucosylated oligosaccharide variants.

Like Genentech’s already well-established product Rituxan (rituximab), Gazyva targets the CD20 surface protein associated with B lymphocytes and is approved to treat chronic lymphocytic leukaemia, one of Rituxan’s main indications. However, head-to-head clinical trials showed it more effective than Rituxan (5). In addition to the technical innovation, Gazyva will presumably also help Genentech stave off inevitable competition from Rituxan-based biosimilars, now that the latter is coming off patent.

Although a first for the US, a glycoengineered, non-fucosylated mAb (Mogamulizumab; used for the treatment of T cell leukemia-lymphoma) has been on the Japanese market since 2012.

Kadcyla represents a second engineered variant of an already approved mAb to come to market in 2012. This drug is Herceptin to which a small cytotoxic molecule (DM1) has been conjugated, and like Herceptin, it is approved for the treatment of HER2-positive metastatic breast cancer. As in the case of Gazyva-Rituxan, Kadcyla’s approval may prove convenient for Genentech in terms of staving off inevitable future biosimilar competition, now that Herceptin is also coming off patent.

A new insulin analogue
Insulin degludec (Novo Nordisk), a new long-acting insulin also made it to market in Europe in 2013, where it is marketed on its own (tradename Tresiba) and as a co-formulation (tradename Ryzodeg) with a well-known rapid acting insulin analogue, insulin aspart. Interestingly, FDA declined to approve the product last year, seeking additional cardiovascular outcome data.

Insulin degludec differs from native human insulin in that the threonine reside at position B30 has been omitted, and more importantly, from a pharmacokinetic point of view, a hexadecanedioic acid has been attached to lysine B29, via a glutamic acid spacer. As a result, the analogue forms multihexameric structures in subcutaneous tissue. Entry into circulation is dependent upon their slow disassociation, in practice conferring duration of action of 42 hours or more on the product, several hours longer that previously approved engineered long acting insulins.

References

1. G. Walsh, Biopharm Int. 26 (4) 54-56 (2013).
2. G. Walsh, Biopharm Int.25 (6), 34-36 (2012).
3. G. Walsh,Biopharm Int. 23 (10), 30-41 (2010).
4. G. Walsh, Biopharm Int. 22 (10) 68-77 (2009).
5. V. Goede, K. et al., New England Journal of Medicine, 370, 1101-1110 (2014)

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