Drug Discovery Today Volume 20, Number 4 April 2015 PERSPECTIVE feature An overview of FDA-approved biologics medicines Michael S. Kinch, [email protected], [email protected] Recombinant DNA technologies revolutionized medicine. Herein, the approvals and mechanistic basis of biologics-based medicines are analyzed. The overall and relative rate of FDA approvals for recombinant proteins grew from the 1980s through the first half-decade of the new millennium. Over time, the number of biologics gaining approval for an orphan indication has climbed to more than 50% in the current decade. The field has been dynamic in terms of the types of biologics, indications targeted and the mechanistic basis of drug activity. Despite impressive increases in recombinant-protein-based medicine, the rate of new biologics approvals could have leveled out. PERSPECTIVE Current analysis concerns that science would outpace society’s established pharmaceutical company (Eli Lilly) Recombinant DNA technology fundamentally ability to control new technology safely. and gained FDA approval for the first recombi- 1 Features changed the way medicines are discovered and Research of more-controversial aspects of nant DNA product (Humulin ; 1982) [5,6]. This developed. In a remarkable convergence of recombinant DNA research was voluntarily sus- aggressive timeline set a standard that continues timing and talent, Stanford University was the pended shortly after the publication of the first to be associated with the biotechnology industry epicenter of a revolution in the early 1970s, papers on recombinant DNA technology. This today. which first led to the concept, and rapidly self-imposed curtailment was an impressive An assessment of biologics drugs over time thereafter the successful demonstration, that demonstration of the potential impact associ- was achieved by compiling a list of all recom- genes from one organism could be isolated and ated with biotechnology, as was the decision of binant biologics-based medicines approved by cloned into vectors for expression in unrelated prominent scientists to request that The National the FDA from 1982 through 2013. Information organisms [1,2]. The resulting scientific Academy of Science evaluated the implications was gleaned initially from the FDA Orange Book knowledge and its commercial applications of the emerging new field of biotechnology [3]. and supplemented with data regarding with- gave rise to the modern biopharmaceutical The resulting Asilomar Conference on Recom- drawn products using the same approaches industry. binant DNA (1975) provided guidelines, many of detailed previously [7]. These results have also This revolution almost did not happen. Wor- which persist today, and gave rise to the ever- been verified against well-established resources 1 ries about the consequences of utilizing tumor- accelerating use of recombinant DNA technol- such as Citeline , PubMed and additional online derived DNA components raised concerns about ogies [4]. resources [8]. Please note that recombinant transmitting cancer among individuals working Within seven years of the Asilomar Confer- products approved outside the USA were not with DNA vectors or recombinant proteins. ence, the first recombinant medicine had been included nor were products (including proteins) Compounding this, popular culture at the time developed and approved by the FDA. Within this purified from sera and other human and non- was highly critical of the potential for science time frame, a key pioneer of recombinant human sources. 1 gone awry. Books and films such as The Biological DNA research (Herbert Boyer) had founded Since the approval of Humulin , a total of 91 Time Bomb (1968), The Andromeda Strain (1969) Genentech (1976), developed a recombinant recombinant-protein-based new molecular en- and Future Shock (1970) had primed public form of human insulin (1978) partnered with an tities (NMEs) have been approved by the FDA as 1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.09.003 www.drugdiscoverytoday.com 393 PERSPECTIVE Drug Discovery Today Volume 20, Number 4 April 2015 TABLE 1 Comparison of small molecule and biologic-based NMEs (1982–2013). NME type Total IND to approval (years) Withdrawn because of safety concerns (%) Small molecule 777 8.5 (n = 200) 26 (3.3%) Biologic 91 7.4 (n = 30) 2 (2.2%) -Monoclonal antibody 34 7.8 (n = 18) 2 (5.9%) -Enzyme modulator 26 5.9 (n = 8) 0 -Receptor modulator 31 8.3 (n = 4) 0 The total number of new molecular entities (NMEs) approved from 1982 through 2013 is indicated, as are the average times from investigational new drug (IND) to approval and the number and fraction of the molecules approved that were subsequently withdrawn for reasons of safety (noninclusive of withdrawals because of obsolescence or lack of sales). Please note that IND submission dates were available only for a relative small proportion of NMEs approved in this time period as indicated in parentheses. therapeutics (Table 1, Fig. 1a). These biologics application of monoclonal antibodies was emerging technologies to enhance drug safety can be almost evenly divided into three cate- hampered by the need to minimize immuno- and efficacy. gories: monoclonal antibodies, replacement or genicity and thus required new breakthroughs. The proportion of biologics-based approvals modulators of enzymes and replacement or A pioneering Cambridge University study (relative to small molecules) generally increased modulators of cell surface receptor function. The demonstrated replacement of murine antibody through the 1980s and 1990s and represented first five approvals within each category are complementarity-determining regions with one-third of all NME approvals in the early 2000s shown in Table 2. human versions and thereby provided a means (Fig. 1b) and again during 2009–2010. Although The first monoclonal antibody, muromonab to decrease immunogenicity [10]. Such break- the absolute number of biologics approvals has CD3, gained approval in 1982 as a murine throughs facilitated approval of the second remained relatively stable (with the exceptions protein approved for use in acute organ trans- monoclonal antibody, abciximab (1993), and noted below), the relative fraction of approvals, plant rejection [9]. The mechanistic basis of thereafter ignited a revolution in protein engi- as compared with small molecules, declined suppressive immune function minimized neering technology. The advances continue over the past three years (2011–2013). One the risk of immunogenicity. However, broad today and include fully human antibodies and potential explanation is that these changes (a) 100 Features Biologics 80 mAb Enzym e PERSPECTIVE 60 Receptor modifier 40 Cumulative NMEs 20 0 1982 1992 2002 2012 Year (b) (c) 35% 60% Biologics 30% 50% Non-bio logics 25% 40% 20% 30% 15% 20% 10% % Biologics NME Orphan approvals 10% 5% 0% 0% 1982 1987 1992 1997 2002 2007 2012 Year 1981-19851986-19901991-19951996-20002001-20052006-20102011-2013 Drug Discovery Today FIGURE 1 Accumulation of FDA-approved biologics. (a) The accumulation of the three major categories of biologics-based new molecular entities (NMEs) is shown over time W since the initial approval of Humulin in 1982. (b) The proportion of biologics-based NMES (relative to all NMEs) is shown on a half-decade basis. (c) The proportion of biologics-based and non-biologics-based orphan approvals is shown over time. 394 www.drugdiscoverytoday.com Drug Discovery Today Volume 20, Number 4 April 2015 PERSPECTIVE TABLE 2 First five biologics approved in major categories. Monoclonal antibody Receptor modulator Enzyme modulator Muromonab CD3 rhInsulin Dornase alfa (Ortho, 1982) (Eli Lilly, 1982) Genentech (1993) Abciximab Interferon alpha-2a Pegaspargase (Centocor, 1993) (Roche, 1986) (Enzon, 1994) Rituximab Epoetin alfa Imiglucerase IDEC (1997) (Amgen, 1989) (Genzyme, 1994) Basiliximab Filgrastim Alteplase (Novartis, 1998) (Amgen, 1991) (Genentech, 1996) Palivizumab Sagramostim Reteplase (MedImmune, 1998) (Immunex, 1991) (Boehringer-Mannheim, 1996) reflect capacity levels within the regulatory restricted to FDA-approved NMEs (and thus 2006. The first enzyme replacement and mod- agency (e.g. FDA Center for Biologics Evaluation could not address the question of how many ulators gained approval in the early 1990s and and Research; CBER). At this early stage, it cannot clinical candidates had been rejected as a result tended to favor metabolic disorders, including be excluded that this recent trend simply reflects of toxicity concerns). Nevertheless, one view of inborn genetic errors of metabolism (Fig. 2c, random chance and it remains to be seen post-approval safety was achieved by assessing other data not shown). The approval rate for whether such findings will persist over the the number of NMEs later withdrawn from enzyme modifiers has been remarkably steady coming years. the market owing to concerns about toxicity over time. The first monoclonal antibodies were To identify factors relevant to the growing (Table 1). When evaluating small molecule pro- approved in the early 1990s but were heavily popularity of biologics, the development and ducts approved since 1982, 3.3% (26 in total) weighted toward oncology and inflammatory regulatory histories of FDA-approved, small- have subsequently been withdrawn because of disorders (Fig. 2d). Like enzyme modifiers, the molecule- and biologics-based medicines were safety concerns. Biologics generally tended to approval rate for new