F E AT U R E

What’s fueling the biotech engine—2011 to 2012
Saurabh (Rob) Aggarwal
Sales in the biologics sector show modest but healthy growth rates for the fourth consecutive year, with cancer drugs garnering the greatest revenues. As the diabetes epidemic grows and innovation of insulins continues, drug companies in that space are moving up in the ranks.
n 2011, the US biotech sector grew modestly, with total sales reaching $53.8 billion, or a 4.9% increase over 2010 sales (Fig. 1a). Driven by rising uptake of monoclonal antibodies (mAbs) and insulin products, this increase was slightly better than the overall pharmaceutical sector, which experienced growth of 3.0% in 2011 (ref. 1). The outlook for 2012–2013 seems to be improving, as several promising products, which are driving the current growth, reach the market (Fig. 1b). However, in the long term, the sector faces increasing difficulties with reimbursement and the potential launch of biosimilars, which could impose downward pressure on unit sales and pricing in this sector. In the following article, I analyze the market trends observed in 2011 and the first half of 2012 for nine classes of biologics (Box 1 and Fig. 2). For each of these classes, I provide a discussion on sales volume, pricing, indication expansions, competition within biologics and from small-molecules drugs, safety issues and promising new candidates. I also provide a ranking of the top companies in terms of the size of US sales of biologics (Box 2 and Fig. 3). On the basis of the sales trends, I have categorized products within each respective therapeutic class as market leaders (where sales are greatest for an indication), rising stars (where sales show rapid growth) or laggards (where sales underperformed). The methodology applied in this article is essentially the same as I used in previous biotech market overviews published in this journal2–4. Blockbuster products are defined as those with US sales of at least one billion dollars. The following sections cover each of the nine classes of biologics in descending order of the sales they accrued.
Saurabh (Rob) Aggarwal is at Novel Health Strategies LLC, Bethesda, Maryland, USA. e-mail: sa2@novelhealthstrategies.com

I

mAbs In 2011, mAbs maintained their ranking as the best-selling class of biologics, with US sales reaching ~$20.3 billion, a 10.1% growth over their 2010 sales (Fig. 2), keeping companies with mAb products in the lead in revenues (Fig. 3). Last year’s growth rate is similar to the growth during 2009–2010 (9.7%). The growth of the mAbs sector would have been greater if it had not been offset by a decline in sales of the mega-blockbuster antibody Roche/Genentech’s (Basel) Avastin (bevacizumab), which was due to the reversal of accelerated approval for breast cancer. If Avastin is excluded from the calculation, the total sales of all mAbs grew by 17% during 2011. $2.0 billion in this growth in sales was driven by several new product launches: Human Genome Sciences (Rockville, MD, USA)/GlaxoSmithKline’s (GSK, London) anti–B-lymphocyte stimulator human mAb Benlysta (belimumab); Seattle Genetics (Seattle)/Takeda’s (Osaka, Japan) anti-CD30 chimeric IgG1 mAb–monomethyl auristatin E conjugate Adcetris (bretuximab vedotin); Amgen’s (Thousand Oaks, CA, USA) human mAb targeting RANK ligand denosumab (Xgevz); and Bristol-Meyer Squibbs’s (New York, USA) anti-PD1 antibody Yervoy (ipilimumab). There are now 36 US Food and Drug Administration (FDA)-approved mAbs, sales of which constitute ~38% of the total biologics market. Ten mAb products constitute 86% of the total sales of this sector (Fig. 4). Among them, six products experienced high double-digit growth, whereas four products either did not change or declined in sales. The mega-blockbuster Remicade (infliximab, Janssen’s (Horsham, PA, USA), which was the first anti-tumor necrosis factor (TNF)-alpha product to be approved in the United States in 1998, had a slight decline in sales, as it lost market share to other rapidly

expanding anti-TNF products, such as Abbott’s (Deerfield, IL, USA) human IgG1 mAb Humira (adalimumab) and UCB’s (Brussels) Cimzia (certolizumab pegol; recombinant PEGylated anti-TNF-alpha humanized mAb fragment). On the other hand, another market leader Genentech/Biogen Idec’s (Cambridge, MA, USA) anti-CD20 chimeric mAb Rituxan (rituximab) grew by 9%, driven by new clinical data from the PRIMA trial supporting longer-duration treatment in lymphoma5. Two other notable mega blockbusters, in terms of their 2011–2012 trends are Humira and Avastin. Last year, Humira gained the status of the best-selling biologic in the United States and globally. In 2011, Humira’s US sales reached $3.5 billion; global sales were $7.3 billion, posting a record 20% sales growth over previous year sales. Humira’s growth is more than double the overall growth rate of the anti-TNF market (~8%), implying that its sales growth was driven by both indication expansion and taking market share from other products. Humira’s nearterm sales catalyst is the newly approved indication for ulcerative colitis, though in the long term, Humira and the anti-TNF market could face some competition from Pfizer’s (New York) small-molecule Janus kinase (JAK-3) inhibitor tofacitinib6, which was approved by the FDA in November 2012. In pivotal trials, including one head-to-head with Humira, tofacitinib showed impressive efficacy in various indications7,8. As an oral product, tofacitinib could be a game changer in this market. The other mega-blockbuster mAb, Avastin, suffered a major setback in 2011, as its sales declined by 13%, falling to $2.6 billion, compared with $3.0 billion in 2010. This decline, which was expected, was mainly due to the FDA withdrawal of its indication for metastatic breast cancer. Near term, there remain two
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nature biotechnology volume 30 number 12 DeCember 2012

According to Roche. FDA approved Perjeta for treatment of patients with HER2positive. All rights reserved. Approved in November 2011 for wet AMD.7 billion.3 $46.9 billion last year. blocks ligand-dependent heterodimerization of HER2 with other HER family members. First. Another blockbuster mAb. positioning it as a potentially cost-effective treatment option compared to Lucentis. USA) Zaltrap (ziv-aflibercept.2 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 2007 2008 2009 Year/quarter 2010 2011 2012 Figure 1 Growth trends in the United States biotech market for biologic drugs (2007–2011). ESAs continue to be the sector’s downfall. Lucentis. reaching $1. is sold at almost a 40-fold price premium. which previously had been approved for agerelated macular degeneration (AMD) under the brand name Eylea.3-mg dose for diabetic macular edema.F E AT U R E Pfizer’s Mylotarg (gemtuzumab ozogamicin) in 2010. Another near-term sales driver for Lucentis is the recent approval of its lower. Benlysta and Perjeta. indicating rapid uptake in the ALCL indication. NY. Eylea’s 2012 US sales are expected to hit $700–750 million. from $14. and Taxotere (docetaxel). Adcetris.4% $51. Zaltrap’s price was reduced by 50%. Lucentis sales grew by 22%. there has been a contraction of the market for growth factors. its sales could further expand in this indication. considered a breakthrough treatment for ALCL. smaller than the market for growth factors ($14. had an overall response rate of 86% in severely ill patients12. thereby. (b) Quarterly sales growth for biologic drugs (2007–Q2 2012).5% 4.2 $53. monthly 0. indicated for relapsed and refractory Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma (ALCL) is the first FDA-approved antibody-drug conjugate therapy since the withdrawal of npg Box 1 Leading and lagging biologic categories Above and beyond the single-digit growth across many categories of biologics. whereas the three topselling mAbs (Humira. another anti-HER2 therapy. showed comparable efficacy but had a limited impact on US sales growth. with insulin analogs accounting for three-quarters of sales. positive catalysts for Avastin—the long-term. it has almost halved. which posted high double-digit growth in 2011 was Roche’s anti-VEGF-A recombinant humanized IgG1 kappa-isotype mAb fragment Lucentis (ranibizumab). According to recent company statements. and in the first half of 2012 they were $69. In 2011. mAb sales were $11.000 per year. when oncologists at Sloan-Kettering strongly criticized the value of the product and decided not to include it in their formulary list11. maintenance setting use in colorectal cancer (based on the TML18147 study9) and the expanding use for ovarian cancer (AURELIA study10). sales of Adcetris were ~$43. Notably. Finally. Lucentis has a new and fierce competitor in Eylea (a fusion protein). As physicians gain more experience with use of this product.5% 3% 4. just four months after launch. (a) Total sales and growth rate trends. in fact. At the American Society of Clinical Oncology’s annual meeting this year in Chicago.5 6. In June 2012.4 billion. hormones were the second-bestselling class of biologics and the top category US sales ($ billions) a 55 50 45 40 35 30 11. Perjeta targets the extracellular dimerization domain (subdomain II) of HER2 and. soluble portions of VEGF 1 and 2 extracellular domains fused to a human IgG1 Fc portion). the results of the comparisons of AMD treatments trial. HER3 and HER4. an engineered version of Avastin. the market for mAbs had grown to $20. Three new mAbs on the market in 2011– 2012 were Adcetris. which compared Lucentis with off-label Avastin in patients with wet AMD. Five years ago. Remicade and Rituxan) sold north of $3 billion each. However. late-stage breast cancer. Seattle Genetics and Takeda presented several studies that showed promising activity of Adcetris in re-treatment of CD30-positive hematologic malignancies and relapsed or refractory CD30-positive.2 million. driven by growth in its use for treatment of wet AMD and the new indication of retinal vein occlusion. sales of mAbs have witnessed explosive growth since 2006. by last year. and likely will continue to be in the coming years as more competing products reach the market. including EGFR.9% 6 4 2 b Quarterly sales growth rate (%) 8 3 –2 2007 2008 2009 Year 2010 2011 0 5.8 12 10 8 Year-over-year growth rate (%) $44. In 2011.1 billion).5 $48. During the first half of 2012. Whereas ALCL is an ultra-orphan indication. A second notable development has been the impressive growth in the market for recombinant hormones. GSK reported sales of $30 million in the United States. Four new entrants to the market contributed $2 billion in sales. Human Genome Sciences/GSK’s Benlysta was approved by the FDA in March 2011 for systemic lupus erythematosus. As directed by the label. its uptake has been much slower than expected. Perjeta must be combined with Herceptin (trastuzumab).2 million. Eylea is priced at a discount. non-Hodgkin’s lymphomas. Inc. © 2012 Nature America. 1192 volume 30 number 12 DeCember 2012 nature biotechnology . Market analysts had forecast that Benlysta’s peak sales will be in the range of $3–4 billion. However.3 billion—so large the class sold ~$8 billion more than any other therapeutic class. albeit at a much lower concentra- tion. which could cost more than $200. who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. Adcetris has potential for broader use in CD30-positive lymphomas.3 2. Hormones In 2011. A new competitor for Avastin in the colorectal cancer indication is Regeneron’s (Tarrytown. some of which will likely be due to gaining shares from Lucentis. US sales of three classes of therapeutic’s are particularly noteworthy. likely due to its first-inclass product status and its unique mechanism of action.1 billion in 2006 to $7. Adcetris.

4 3.F E AT U R E in terms of sales growth.4 $3. Among them. The story is not all of winners. more than double its 2010 sales. all grew by high double-digit rates (11–24%) during 2011. largely from expanding indication of its top-selling drug. Sanofi’s GLP-1 analog lixisenatide and Eli Lilly/Boehringer Ingelheim’s (Ingelheim. Avastin and from sales of Lucentis in the large wet AMD market.4 billion in 2006.2 billion behind in US sales reveals how much ground the Thousand Oaks biotech has lost. Two other companies that have seen impressive growth and movement up the rankings are Novo Nordisk and Sanofi. from $7 billion to $11. ultra-long-lasting insulin Degludec and insulin combination analog DegludecPlus.8 billion. Roche’s acquisition of Genentech in 2009 has catapulted the big pharma company to 2nd place overall in US biologic sales (before the merger.4 –10. which would be a great advancement over current long-acting insulin analogs13. With several new drugs in late-stage development—a new osteoporosis drug and a cholesterollowering drug—Amgen might retain its top post in the coming years.3 –5.9 billion. Eli Lilly’s (Indianapolis) Humalog (insulin lispro) and Sanofi Aventis’s (Paris) long-acting insulin Lantus (insulin glargine).7 billion five years ago to $4.9 $1. This sector had previously experienced major events related to safety issues and reimbursement. as it has the advantage that it can last up to 40 h.2 billion in 2006 to a low of $12 billion in 2009 (they have since bounced back a little to $12.1 $1. Inc.8 0. however. this category did not experience much growth until the FDA approved Novo Nordisk’s Victoza (liraglutide) and Bydureon. Lantus is the second-best-selling megablockbuster biologic drug in the United States. a 16% increase over its 2010 sales.2 14.5 billion for interferons). with growth in all major product lines.3 4.8 –10.3 6.2 4. All rights reserved. the Swiss company had US sales of only $0.9 billion. Amylin’s (now Bristol-Myers Squibb (BMS).9 13.3 $0. Another category of biologics for diabetes that has experienced rapid growth is GLP-1 analogs. A long-term catalyst for Lantus is potential combination with Sanofi’s glucagonlike peptide 1 (GLP-1) candidate lixisenatide. The rapid sales growth of hormones was mainly driven by high double-digit growth in insulin analogs. Last year. (b) Growth rates of the categories in 2010 and 2011. its revenues slipped from $14.1 0.4 © 2012 Nature America. and is now facing new lower-priced competitors. Trends for Q1 and Q2 2012 show further high single-digit declines in sales of this sector. 2 and 6). 3) over the past five years reveal that several companies have outperformed their counterparts and growth of the sector as a whole.8 mAbs Hormones Growth factors Fusion proteins Cytokines Blood factors Therapeutic enzymes Recombinant vaccines Anti-coagulants Other $20. which fell to $7.3 4. Several new drugs are expected in the diabetes market. However. Johnson & Johnson sales have declined since a high of $5. moving from 7th place in 2006 to 5th place in 2011. Amgen sold $7 billion more product than any other company. Victoza’s sales reached $640 million.5 billion. FDA advisory committee voted to approve Degludec.3 $7.9 10. Sanofi has shown even greater growth. because Byetta had to be injected twice daily and came with a safety warning.0 3. their sales reached $13. with only slightly different sales from Abbott’s Humira. Three blockbuster products in this sector are Novo Nordisk’s (Bagsvaerd. Since 2006.4 billion at an overall growth rate of 14.4 20.9 4.5 11.9 $12.6 4. nature biotechnology volume 30 number 12 DeCember 2012 1193 . Victoza is expected to reach billion dollar sales in 2012. could further add to Sanofi’s bottom line.0 billion in 2011. Rituxan.8 billion.1 billion in 2006 (Figs. New York) Byetta was the only GLP-1 analog on the market. Figure 2 Top nine categories of biologic drugs in terms of US sales in 2011.5 11.2 1. so those sales were estimated assuming 20–30% of worldwide sales were generated in the United States.4% year over year (Figs.1 4. Novo has grown its US sales from $1. Denmark) Novolog (insulin aspart). Although Amgen (just) remains the company with the largest US sales of biologics. including Novo Nordisk’s a $0.3 1. a once-daily formulation of Byetta.2 1.4 9. with sales of insulin (Lantus) boosting revenues in the United States from $1. with its cadre of enzyme replacement therapies.0 10. In 2011. In 2011. Lantus’s US sales reached $3. almost half the peak sales of $14. and the major driver for this sector’s sales.7 13. Last year. The red boxes indicate the categories showing the fastest growth rate during that period. 2 and 5). countering losses with its once blockbuster Epogen (epoetin alpha)). US sales of insulin products reached $9. which are likely to continue to put downward pressure on sales.9 4.2 0.9 0. Manufacturers of therapeutic enzymes do not break out US sales. Degludec is the most anticipated new product in diabetes.0 7. These sales npg Box 2 Five years of company rankings Sales trends (Fig. constituting 75% of hormone sales. The addition of the Genzyme franchise.2 $4.3 12. Growth factors 2011 marked the sixth year of continuous decline in sales of growth factors. (a) US sales ($ billions) of these drug categories. Germany) long-acting insulin analog LY2605541.2 7.5 billion. In 2006. the fact that Roche is now just $0.1 14. Until 2009.1 1.2 b US sales ($ billions) Growth rate (%) 2010 2011 2010 2011 mAbs Hormones Growth factors Fusion proteins Cytokines Blood factors Therapeutic enzymes Recombinant vaccines Anti-coagulants 18.2 $4.6 –2. In November 2012. which can be combined because of their complementary mechanisms of action.3 billion to $3. Genentech has grown its US sales by nearly $5 billion.

4 $1.0 –4. $3.8 billion. reaching $4. was a landmark event ending an almost two-decade-long monopoly by Amgen (Thousand Oaks.4 0.9 3.3 billion (Fig.2 20.4 15.7 1. although the majority of these sales (~80%) US sales ($ billions) npg a $0.0 17.5 8. Mircera (methoxy polyethylene glycolepoetin beta). Erbitux US sales were split 40/60 between Lilly and BMS.1 3.0 10.9 3.4 3. During the next 2–3 years. it could lead to price declines and lower sales in this category.5 $1. all mAbs with sales <$300 million per year. MA. Red boxes indicate companies that had biologics sales growth of >10%. $12. The double-digit increase in Neulasta’s price was likely due to the expected launch of new cheaper CSF products. CSF sales in the United States grew by 10%. However.4 –2. In addition.0 0 Leader: Humira $2. with sales falling by another 25% in 2011.4 1.5 2011 2. biosimilar products of Hospira (Lake Forest.5 12.0 2.7 4. This year.5 $1. the FDA’s approval of Affymax (Palo Alto. (b) Annual growth rates of the top ten companies. as >80% of the dialysis centers are managed by two service providers.2 0 2007 2008 2009 2010 $0.7 2011 12. with market share as high as 80% in some European Union markets. Teva (Tel Aviv) and Sandoz (Holzkirchen. Data for 2011–2012 from the US Renal Data System show that intravenous iron use (which provides cost savings over ESA) as well as transfusion rates have increased.2 0.0 billion in 2011.7 US sales ($ billions) Growth rate (%) 2010 12.0 2011 Laggard: Herceptin US sales ($ billions) 2.3 billion of US sales. This increase was largely due to a price increase for Amgen’s recombinant form of granulocyte colonystimulating factor Neulasta (pegfilgrastim) with sales of $3. reaching $4.9 Novo Nordisk. Amgen signed a seven-year Epogen sales agreement with DaVita.5% in 2011.0 Remicade 4.7 $0. The ESA market has declined substantially over the past five years.5 Amgen.8 16.4 © 2012 Nature America.5 $3.5 5.4 7.6 0.7 $2.0 billion. Rituxan US sales have been split equally between Genentech and Biogen Idec. Germany) could escalate price wars in this market. USA) and DaVita (Denver). which has reversed the incentives for prescribing these products.3 Lilly BMS Merck Figure 3 Companies with the top sales of biologic drugs in 2011.3 $0. which could take a considerable share from Amgen’s products.0 3.5 $0. a major event related to CSF products was the FDA approval of Teva’s Neutroval (tbo-filgrastim). USA). (a) 2011 sales for US markets for mAbs ($ billions). 2).1 0. from overusing to underusing. $12. as more providers are using fewer ESAs14. more ESA products could be launched in the United States.3 $3.8 2010 1. following an aver- age sales price increase of 10.2 12.3 $1. Ten fusion proteins are currently in the market. (a) Total US sales (in $ billions) of the top 13 companies. (b) Trends in US sales show Humira leading.0 $1. b Amgen Roche J&J Novo Nordisk Sano Abbott Biogen Idec J&J. volume 30 number 12 DeCember 2012 nature biotechnology .3 13.3 4. Fresenius (Waltham. For the purpose of this analysis. $4. biosimilar CSFs have been highly successful.7 6.2 1.4 $0. CA. most falling into the category of erythropoietin-stimulating factors (ESAs) and colony-stimulating factors (CSFs). Lilly BMS AstraZeneca belong to 13 brands of growth factors (12 original molecules) currently available in the United States.0 1. which was expected to be approved through the new biosimilars pathway. USA) in this market.8 $1.6 Humira b $2.0 3. $3.2% between Q1 2011 and Q1 2012.4 Sano . Teva used the full Biologics License Application process to seek approval for this product. the uptake of a new ESA is compounded by the unique structure of this market. Genentech comprised $11. Inc. Fusion proteins The sales of this sector grew by ~6. Last year.5 2007 2008 2009 2010 2011 $3.F E AT U R E a Abbott.7 $1. ‘Others’.8 6. IL.0 0 2007 2008 2009 2010 2011 Figure 4 Trends in US sales of mAbs.0 Rituxan Avastin Rising star: Stelara US sales ($ billions) Lucentis Herceptin Synagis Erbitux Xolair Stelara Others 0. Stelara rising and Herceptin lagging.7 7.9 $3.8 3. The recent decline was due to the bundling of payments by the US Centers for Medicare & Medicaid Services.0 6.5 2. $3.2 $1. approved since 2007 by the European Commission but held up in the United States because of a patent dispute with 1194 Amgen.6 $2. especially Roche’s third-generation ESA. In some markets outside the United States.5 2011 US Sales—Companies Amgen Genentech Novo Nordisk Abbott Roche J&J Sano Biogen Idec Serono AstraZeneca Biogen Idec.4 $1.3 –14. reaching $3.1 3. $4.7 3.1 Roche. However. as happened in several European markets. All rights reserved. a peptide EPO mimetic.5 3.4 $0.8 billion of Roche’s $12. CA.0 1. USA)/Takeda’s Omontys (peginesatide). As biosimilar CSFs are launched in the United States. In 2012.7 12.

Israel) Elyeso (taliglucerase alfa) become the third product to be approved for this indication. Future outlook for IFN-b products looks weak.0 2. driven by 16–20% price increases for all three marketed brands.4 $3. forcing payers to dramatically increase use of various types of prescription utilization controls (e.3 $1. a decline of 10% over their 2010 sales (Figs. sales of IFN-b increased by 5%. 2 and 8a).2 $0. which could lead to important cost savings for payers and patients. 2 and 7a). 2 and 7b). recombinant human beta-glucocerebrosidase containing a His495 Arg substitution). Nulojix is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of cytotoxic T-lymphocyte antigen 4 (CTLA4).F E AT U R E belong to Amgen’s Enbrel (etanercept. recombinant human glucocerebrosidase produced by gene-activation technology) more than doubled. Three blood factors make up this market: factor VIII. an anti-inflammatory with neuroprotective action. IFN-b brands are the biggest sellers in the cytokines markets.9 $2. Zaltrap Regeneron’s third FDA-approved.g. differing only by two amino acids. Last year.1 1. Blood factors Blood factors is one of the smaller markets in the biologics sector.8% in 2011 (Figs.6 $0. MA. It is an engineered version of another BMS product called Orencia (abatacept). (fingolimod) and Biogen Idec’s (Cambridge. constituting 79% of the total sales of this sector. 1195 npg nature biotechnology volume 30 number 12 DeCember 2012 .5 0.5 $1. largely driven by price increases (Figs.8 $0. Interestingly. Their sales declined by 5. All rights reserved. Elyeso is priced at a 25% discount to Cerezyme. Therapeutic enzymes Therapeutic enzymes are ultra-orphan therapies that are indicated for a few hundred to 1.5 $0. which have longer half-lives than previous versions—engineered with Fc fusion.3 2008 2009 2010 2011 3. This category has struggled in sales due to manufacturing woes and competition from newer. both indicated for MS. Notable ones in phase 3 clinical development are Biogen Idec’s Factor VII-Fc and Factor IX-Fc and CSL Behring’s (King of Prussia. ‘Others’. leucovorin and irinotecan (Camptosar) (a regimen called FOLFIRI). sales of which grew by 4. they could drive higher sales in this category. who are resistant to. This year. Zaltrap’s peak sales in this indication are expected to be in the range of $250–300 million. which require starting treatment with the most costeffective drug before moving to more costly therapies). In 2011.0 $0. indicated for use in combination with 5-fluorouracil.000 patients. respectively.7 $2.3 $0.0 $2. 25% and 43% of total sales. the carrot cell culture system uses disposable.0 2.0 $0.2 2007 US sales ($ billions) 0.7 2007 2008 2009 2010 2011 Rising star: Levemir 1. Zaltrap is a recombinant fusion protein that binds to VEGF-A. sales of the 11 recombinant therapeutic enzymes fell to $1.7 $2. USA) vascular endothelial growth factor trap Eylea (afilibercept). VEGF-B and placental growth factor. As an anti-TNF product. a fusion protein comprising the extracellular domain of human p75 TNF-alpha receptor linked to the Fc portion of human IgG1). Figure 5 Trends in US sales of recombinant hormones.0 3.2 $0. Biogen Idec’s BG-12 (dimethyl fumarate). Three new fusion products were launched this year: Zaltrap. 3 and 8a). Enbrel has lagged behind in this high-growth market and has been losing new market share to Abbott’s Humira.3 $0.1 $2.0 Rising star: Novolog $1. prior authorization and step edits15. assuming 25–30% of worldwide sales were generated in the United States.6 $3. In the pipeline are next-generation versions of factor VII and factor IX products.2 billion in 2011 (Figs. MA. all hormones with sales of <$200 million per year.4 US sales ($ billions) $1. driven by premium pricing and increased utilization. factor VIIa and factor IX. In 2010–2011. as another promising small molecule nears approval. Pfizer/Protalix’s (Carmiel. drug. or have progressed following. Four kinds of cytokines are currently available—interferon (IFN)-a indicated for hepatitis C. sales of Shire’s (Basingstoke.5%.1 billion. for patients with metastatic colorectal cancer.4 $0. Nulojix is the first selective T-cell co-stimulation blocker indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. driven by lower sales of factor VIIa.5 b US sales ($ billions) Lantus Novolog Humalog Humulin Levemir Victoza Byetta Nutropin Novolin Genotropin Follistim Humatrope Norditropin Others Leader and rising star: Lantus 4. US sales of cytokines grew to $4. ing because of competition from Novartis’s (Basel) small-molecule Gilenya. lower-priced therapies. their manufacturers do not break out the US sales.7 $0. constituting 32%.0 $3.0 0. Nulojix’s peak sales are expected to be ~$500 million. stealing a large share from Genzyme’s (Cambridge. USA) albumin-conjugated Factor IX.0 1. For most of these products.0 0. (a) 2011 sales in US market for recombinant hormones ($ billions). so I have provided an estimate. PA. IFN-b unit sales have been declin- a $0.1 $0.7 $1.2 $2. Cytokines In 2011. UK) Vpriv (velaglucurase a. an oxaliplatin-containing regimen. Inc. Vpriv is priced at a 15% discount and is the second biologic product to be indicated for type 1 Gaucher disease.5 $0. Elyeso is the first approved biologic to be produced using plant cells. USA) Cerezyme (imiglucerase.2 billion. IFN-g and the interleukins.8 $0. IFN-b is the only top-selling category to grow by tripledigit rates from 2007–2011. driven by price increases. making this market vulnerable to price wars and share gains. IFN-b for multiple sclerosis (MS). USA) Tysabri (natalizumab. The seven brands that make up this category generated US sales of ~$1. albumin or pegylation—and thus could reduce the frequency of injection for patients and improve their overall quality of life. As these products reach the market. (b) Trends in US sales show Lantus. Levemir and Novolog rising. unit-wise its sales have declined by 1–2%. humanized mAb against the cell adhesion molecule a4-integrin). Two notable trends in this sector are the uptake of lower-priced products and launch of new branded products.0 2007 2008 2009 2010 2011 © 2012 Nature America.. BMS’ Nulojix (belatacept) and Regeneron/Sanofi’s (Bridgewater NJ.

biologics for cancer treatment generated $13. Lundbeck’s (Copenhagen) Desmoteplase (a recombinant tissue plasminogen activator based on a protein found in vampire bats).0 $3. Last year. is more specific for fibrin.0 a $0. The growth in sales was driven by the expanding use of existing products for oncology.0 US sales ($ billions) $3. NJ. (b) Blood factors are dominated by two brands. 24% over its 2010 sales. All rights reserved. The higher sales were driven by its being prescribed for males. (b) Trends in US sales show Neulasta rising. recombinant tissue plasminogen activator). such as Avastin and ESAs. overall US sales of biologics grew modestly by 5–6%.0 $3. when they are derived from Escherichia coli. and Medivation’s (San Francisco) small-molecule androgen antagonist Xtandi (enzalu- npg a $0.5 $2.3 $1. their high price ($50. Provenge sales for Q1 and Q2 were $161 million. Conclusions During 2009–2011.3 Avonex Rebif Betaseron Pegasys Other b $1. 2 and 8c). all hormones with sales of <$200 million per year.6 $0.5 $0. Last 1196 year.0 $1. volume 30 number 12 DeCember 2012 nature biotechnology . However.0 3. In the United States alone. which lacks the lysinebinding Kringle 2 domain.0 2.0 2.1 2007 2008 2009 2010 2011 Leader: Neulasta $0. as analysts had forecast that peak US sales of Provenge could reach $3–4 billion16. which constitutes 71% of sales in this sector.1 $3. the sales growth would have been almost double if it had not been offset by the decline in sales of blockbuster products. indicated for patients with acute lymphoblastic leukemia. USA) oral small-molecule inhibitor of 17 alpha-hydroxylase/C17.3 Figure 7 US sales of cytokines and blood factors ($ billions). High sales in oncology are due to substantial unmet needs for various cancers and the relatively high price of cancer drugs (average cost 2007 2008 2009 2010 2011 Laggard: Epogen 4.000–100. Recombinant vaccines During 2011. NJ.20 lyase Zytiga (abiraterone).0 2. reaching $395 million (Figs. sterile.0 © 2012 Nature America. which may be less prone to the contamination problems that have plagued this category in the past. 2007 2008 2009 2010 2011 Figure 6 Trends in US sales of growth factors. Sanofi’s taxoid Jevtana (cabazitaxel).0 1.0 1. Provenge consists of autologous antigen–presenting cells stimulated ex vivo with a fusion of prostatic acid phosphatase and granulocytemacrophage colony-stimulating factor. has a longer half-life and is safer to use. Another new product approved in this market is Jazz Pharmaceutical’s (Dublin) Erwinaze. Last year’s US Centers for Disease Control’s Advisory Committee on Immunization Practices voted in favor of expanding the routine use of Gardasil to adolescent boys. its sales rose by 11%.1 $2. Anticoagulants The thrombolytics and anticoagulants segment is the smallest biologics market. Erwinia chrysanthemi. reaching $860 million.4 Novoseven Bene x Other $0.0 0.8 $1. Aranesp and Epogen lagging.2 Laggard: Aranesp $2. Provenge’s uptake is still below expectations. During 2012. which represents a slower-thanexpected uptake.000) is likely to influence physicians and payers to use only the most cost-effective products. Dendreon reported that Provenge sales were $228 million. driven largely by higher sales of Dendreon’s (Seattle) Provenge (sipuleucel-T) and Merck’s (Whitehouse Station. 16 and 18) recombinant vaccine) (Figs.6 $0.1 US sales ($ billions) $2. 11.2 $1.0 3.7 $3. (a) 2011 sales in US market for growth factors ($ billions). diabetes and autoimmune disorders and a dozen new products launched in 2011 and 2012. Notably. the therapeutic enzymes category could experience growth as more products reach the market.0 3.0 0. Inc.5 $2.0 Neulasta Epogen Aranesp Neupogen Procrit Other 4. including Johnson & Johnson’s (New Brunswick.0 tamide). Gardasil’s sales in 2011 were $411 million. Oncology remains the best-selling indication for biologics and the overall pharmaceutical sector (in the United States and globally). USA) Gardasil (human papillomavirus quadrivalent (types 6. recombinant vaccines sector sales experienced 14% growth.1 $0. a substantial increase over its 2010 sales of $48 million. flexible.0 1. (a) Cytokines sales showing the top four brands. In the pipeline is the next-generation version of anticoagulant.2 billion in sales.7 $1.0 $3.6 $2.1 $3. In the long term.F E AT U R E b US sales ($ billions) 4. though this category is experiencing price wars as some indications are getting crowded. ‘Others’. and is pegylated. 2 and 8b). Although they are all complementary therapies. This increase was due to a 26% increase in sales of Genentech/Roche’s Activase (alteplase. who have developed an allergy (hypersensitivity) to chemotherapy drugs asparaginase and pegaspargase.0 $2.1 $1. polyethylene bioreactors. Three new prostate cancer therapies have entered the market that are indirectly in competition with Provenge. Erwinaze is an asparaginase produced in a different host system.0 0.

open-label.000 patients17. Based on sales growth of insulin analogs and new product pipeline. P. American College of Rheumatology (ACR). Garber. Nat.S.6 million in 1980 to 20. P. B. Aggarwal. 367. recombinant vaccines and anticoagulants ($ billions). phase 2 trial. 14 October 2012 12. The impact of biobetters on the insulin market has been discussed above. RANK-L). 508–519 (2012). as the prevalence of diagnosed cases of diabetes in the United States has quadrupled from 5. 17. an oral Janus kinase inhibitor. indicated for rheumatoid arthritis. the price wars are likely to escalate. Insulin analogs for diabetes generated ~$10 billion in US sales in 2011. So-called biobetter insulin analogs (rapid acting. R. IMS Health Top-Line Market Data. Nat. R. 29. 5. 29. C. Two new products for type 1 Gaucher disease. once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week. Engl.J.9% of the population18. which makes any product a blockbuster.2 billion in sales in 2011. several new-product launches have shown promising sales. Last year. Newer pen formulations and longterm safety data have also enabled greater use of these products.2 $0.. pricing wars and reimbursement. S. Bevacizumab beyond progression prolongs survival in metastatic colorectal cancer. presented at15th Annual European Congress. ’Others’.2 b $0. This growth is driven by the expansion of indications and use of these products in chronic long-term settings. costs matters. Sandborn.E.000 per year). This is the only indication that has grown by high double-digit rates continuously for the past decade. Hamlin. Aggarwal. CSFs for neutro- a $0. 5845–5849 (2012). 13. S. Biotechnol.3 $0. <http://www.000– 10. American Society of Hematology (ASH) and Biotechnology Industry Association (BIO) for providing support for this article. Yervoy (human mAb agonist of CTLA-4). representing an increase from 2.S. American Heart Association (AHA). high risk or more complex indications (e. Zaltrap and Perjeta) could drive up the future sales of the biotech sector. 924–931 (2011). Heitz. a fully human mAb targeting the receptor activator of NF-kappaB ligand. 18. 7. Three common challenges to top blockbuster products are the potential launch of biobetters or biosimilars. An estimated 27% of people over 65 have diabetes1. Insulin degludec. Pfizer’s JAK inhibitor sails through phase 3 in rheumatoid arthritis. DC. 987–993 (2009). a growth of 16% over their 2010 sales. The anti-TNF market has been growing by high single-digit rates for the past five years.com/publications/the-pinksheet/72/018/dendreon-readies-for-next-provengehurdles-supply-and-reimbursement> (3 May 2010).. if it is indicated for 5.A. 27.1 $0. 8. Rev. an ultra-long-acting basal insulin. J.org/2012/pres/USDialysisBundle_impact_ NKFCM2012. As more biosimilar products reach the market. Impact of 2009–2011 global health care reforms on pricing. as payers are changing formulary coverage of expensive biologics. Engl.2 $0. Based on the rich pipeline of biologic candidates.g. et al. Med. Aggarwal. human growth hormone for growth deficiency or mAbs for cancer) are likely to have slower or low uptake. K. Lilly and Sanofi have benefited several patient groups and improved their outcomes. 467–468 (2011). 29. long acting and mixtures) and pen formulations developed by Novo Nordisk. Saltz. 367.A. penia) could gain rapid uptake. Med. randomised.usrds. USA. Rep. This high sales growth is due to an epidemic of this disease. 427–428 (2010). Washington. Aggarwal. nature biotechnology volume 30 number 12 DeCember 2012 1197 . in active ulcerative colitis. Bach. 723–735 (2012). Clin. 1. 616–624 (2012). Engl. (c) The recombinant anticoagulants market is dominated by two brands. More than 90% of these sales belong to anti-TNF products.1 Fabrazyme Elaprase Gardasil Recombivax HB Provenge Cerezyme Vpriv Others Pulmozyme Replagal Pediarix Others Activase Xigris Others Figure 8 US sales of therapeutic enzymes. all hormones with sales of <$50 million per year.. 1165–1171 (2010).. Biotechnol. 1083–1089 (2011). Access. Germany. newer biologics cumulatively generated multibillion dollar sales. Biotechnol. S. Some of these products and other recent launches (e. Nat. Inc. 2012. 9. Food and Drug Administration approval summary: Brentuximab Vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large cell lymphoma.J. et al.B. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.5% to 6. Adv.2 $0. N. Podium Presentation UT2 presented at International Society for Pharmacoeconomics and Outcomes Research 17th Annual International Meeting. some of the top blockbuster products will also likely face competition from lower-priced copies. 3. N. Zinman. Targeted cancer therapies. November 3–7. Biotechnol.g. Is maintenance rituximab now ready for PRIMA-time? Curr. J.elsevierbi. passing high costs to patients. Lancet 377. van Vollenhoven. biosimilars for low-risk indications (e.4 $0.2 $0. et al. 4. Based on trends outside US markets. imshealth. 11. 12.F. adding substantial growth to the biotech sector. Helwick. Collins. Products with $100-millionplus sales are Xgeva/Prolia (denosumab. Bevacizumab in the treatment of ovarian cancer. Stelara. AcknowledgementS SA thanks American Society of Clinical Oncology (ASCO). The past 200 years in diabetes. npg © 2012 Nature America. 19. Med. Nat. F. Aggarwal. whereas biosimilars for end-of-life care.1 $0.1 c $0. offered 15% and 25% discounts. psoriasis and ulcerative colitis.pdf> 15. A. Ther. J. Uptake and Utilization Management of Multiple Sclerosis Products in the United States.g. 10. 16. 14.com/portal/site/ims> 2. Dendreon readies for next Provenge hurdles: supply and reimbursement. All rights reserved. it is likely that diabetes could soon overtake autoimmune disorders as the second-top-selling indication. it is likely that oncology will remain the top-selling sector and one of the leading growth drivers of this sector. Autoimmune diseases represent the second-largest market for biologics. “In cancer care. generating $11. Victoza and Provenge. <http:// www. W. 6. K. et al.2012. L. Reimbursement is also becoming an issue across all products. 18. 1332–1340 (2012). de Claro. What’s fueling the biotech engine—2008. American Association of Liver Diseases (AASLD). On a positive note. June 2–6. Tofacitinib. Drug Discov. The high growth of biologics for diabetes has helped Novo Nordisk. Aggarwal. 9. The ASCO Post 3 (15 July 2012). Adcetris.1 $0. Hayes. What’s fueling the biotech engine-2009–2010. R. Abstract PND72.1 $0. 2012). Nat. 367. (a) Therapeutic enzyme sales of the top six brands. E. S. N. The Pink Sheet Daily 71 <http://www. Eylea.1 $0. S.” NY Times. Diabetes is the indication with the thirdhighest sales for biologics and the overall pharmaceutical sector (in the United States and globally). access and health outcomes strategy. Polonsky.1 $0. Berlin. and Wittes. Cancer Res. U. launched in 2011–2012. With the recent establishment of a US regulatory pathway for biosimilars. What’s fueling the biotech engine—2010 to 2011.F E AT U R E is $100. Oncol.B. et al. 355–357 (2010). with high coinsurance19. Sanofi and Lilly move up the company ranks in this sector.9 million in 2010.. 28. ESRD Payment Policy Changes: The New “Bundled” Dialysis Prospective Payment System in the United States (US Renal Data System. (b) Recombinant vaccines sales of top four brands. S.