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Whats fueling the biotech engine2011 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 20122013 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 journal24. 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

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 years growth rate is similar to the growth during 20092010 (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/Genentechs (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)/GlaxoSmithKlines (GSK, London) antiB-lymphocyte stimulator human mAb Benlysta (belimumab); Seattle Genetics (Seattle)/Takedas (Osaka, Japan) anti-CD30 chimeric IgG1 mAbmonomethyl auristatin E conjugate Adcetris (bretuximab vedotin); Amgens (Thousand Oaks, CA, USA) human mAb targeting RANK ligand denosumab (Xgevz); and Bristol-Meyer Squibbss (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, Janssens (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 Abbotts (Deerfield, IL, USA) human IgG1 mAb Humira (adalimumab) and UCBs (Brussels) Cimzia (certolizumab pegol; recombinant PEGylated anti-TNF-alpha humanized mAb fragment). On the other hand, another market leader Genentech/Biogen Idecs (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 20112012 trends are Humira and Avastin. Last year, Humira gained the status of the best-selling biologic in the United States and globally. In 2011, Humiras US sales reached $3.5 billion; global sales were $7.3 billion, posting a record 20% sales growth over previous year sales. Humiras 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. Humiras 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 Pfizers (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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Pfizers Mylotarg (gemtuzumab ozogamicin) in 2010. Adcetris, considered a breakthrough treatment for ALCL, had an overall response rate of 86% in severely ill patients12. Whereas ALCL is an ultra-orphan indication, Adcetris has potential for broader use in CD30-positive lymphomas. At the American Society of Clinical Oncologys annual meeting this year in Chicago, 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, non-Hodgkins lymphomas. In 2011, sales of Adcetris were ~$43.2 million, and in the first half of 2012 they were $69.2 million, indicating rapid uptake in the ALCL indication. Human Genome Sciences/GSKs Benlysta was approved by the FDA in March 2011 for systemic lupus erythematosus. During the first half of 2012, GSK reported sales of $30 million in the United States. Market analysts had forecast that Benlystas peak sales will be in the range of $34 billion. However, its uptake has been much slower than expected, likely due to its first-inclass product status and its unique mechanism of action. As physicians gain more experience with use of this product, its sales could further expand in this indication. Perjeta targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. In June 2012, FDA approved Perjeta for treatment of patients with HER2positive, late-stage breast cancer, who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. As directed by the label, Perjeta must be combined with Herceptin (trastuzumab), another anti-HER2 therapy, and Taxotere (docetaxel), which could cost more than $200,000 per year. Hormones In 2011, hormones were the second-bestselling class of biologics and the top category

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Figure 1 Growth trends in the United States biotech market for biologic drugs (20072011). (a) Total sales and growth rate trends. (b) Quarterly sales growth for biologic drugs (2007Q2 2012).

2012 Nature America, Inc. All rights reserved.

positive catalysts for Avastinthe long-term, maintenance setting use in colorectal cancer (based on the TML18147 study9) and the expanding use for ovarian cancer (AURELIA study10). A new competitor for Avastin in the colorectal cancer indication is Regenerons (Tarrytown, NY, USA) Zaltrap (ziv-aflibercept; soluble portions of VEGF 1 and 2 extracellular domains fused to a human IgG1 Fc portion), which previously had been approved for agerelated macular degeneration (AMD) under the brand name Eylea. Notably, Zaltraps price was reduced by 50%, just four months after launch, when oncologists at Sloan-Kettering strongly criticized the value of the product and decided not to include it in their formulary list11. Another blockbuster mAb, which posted high double-digit growth in 2011 was Roches anti-VEGF-A recombinant humanized IgG1 kappa-isotype mAb fragment Lucentis (ranibizumab). In 2011, Lucentis sales grew by 22%, reaching $1.7 billion, driven by growth in its use for treatment of wet AMD and the new indication of retinal vein occlusion. Lucentis, an engineered version of Avastin, albeit at a much lower concentra-

tion, is sold at almost a 40-fold price premium. According to Roche, the results of the comparisons of AMD treatments trial, which compared Lucentis with off-label Avastin in patients with wet AMD, showed comparable efficacy but had a limited impact on US sales growth. Another near-term sales driver for Lucentis is the recent approval of its lower, monthly 0.3-mg dose for diabetic macular edema. However, Lucentis has a new and fierce competitor in Eylea (a fusion protein). Approved in November 2011 for wet AMD, Eylea is priced at a discount, positioning it as a potentially cost-effective treatment option compared to Lucentis. According to recent company statements, Eyleas 2012 US sales are expected to hit $700750 million, some of which will likely be due to gaining shares from Lucentis. Three new mAbs on the market in 2011 2012 were Adcetris, Benlysta and Perjeta. Adcetris, indicated for relapsed and refractory Hodgkins lymphoma and systemic anaplastic large-cell lymphoma (ALCL) is the first FDA-approved antibody-drug conjugate therapy since the withdrawal of

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Box 1 Leading and lagging biologic categories

Above and beyond the single-digit growth across many categories of biologics, US sales of three classes of therapeutics are particularly noteworthy. First, sales of mAbs have witnessed explosive growth since 2006. Five years ago, mAb sales were $11.4 billion, smaller than the market for growth factors ($14.1 billion); by last year, the market for mAbs had grown to $20.3 billionso large the class sold ~$8 billion more than any other therapeutic class. Four new entrants to the market contributed $2 billion in sales, whereas the three topselling mAbs (Humira, Remicade and Rituxan) sold north of $3 billion each. A second notable development has been the impressive growth in the market for recombinant hormones, with insulin analogs accounting for three-quarters of sales. Finally, there has been a contraction of the market for growth factors; in fact, it has almost halved, from $14.1 billion in 2006 to $7.9 billion last year. ESAs continue to be the sectors downfall, and likely will continue to be in the coming years as more competing products reach the market.

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in terms of sales growth. Last year, their sales reached $13.4 billion at an overall growth rate of 14.4% year over year (Figs. 2 and 5). The rapid sales growth of hormones was mainly driven by high double-digit growth in insulin analogs. Last year, US sales of insulin products reached $9.8 billion, constituting 75% of hormone sales, and the major driver for this sectors sales. Three blockbuster products in this sector are Novo Nordisks (Bagsvaerd, Denmark) Novolog (insulin aspart), Eli Lillys (Indianapolis) Humalog (insulin lispro) and Sanofi Aventiss (Paris) long-acting insulin Lantus (insulin glargine); all grew by high double-digit rates (1124%) during 2011. Lantus is the second-best-selling megablockbuster biologic drug in the United States, with only slightly different sales from Abbotts Humira. In 2011, Lantuss US sales reached $3.5 billion, a 16% increase over its 2010 sales. A long-term catalyst for Lantus is potential combination with Sanofis glucagonlike peptide 1 (GLP-1) candidate lixisenatide, which can be combined because of their complementary mechanisms of action. Another category of biologics for diabetes that has experienced rapid growth is GLP-1 analogs. Until 2009, Amylins (now Bristol-Myers Squibb (BMS), New York) Byetta was the only GLP-1 analog on the market. However, because Byetta had to be injected twice daily and came with a safety warning, this category did not experience much growth until the FDA approved Novo Nordisks Victoza (liraglutide) and Bydureon, a once-daily formulation of Byetta. In 2011, Victozas sales reached $640 million, more than double its 2010 sales. Victoza is expected to reach billion dollar sales in 2012. Several new drugs are expected in the diabetes market, including Novo Nordisks

$0.9 $1.1 $1.2 $4.2 $4.3

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2012 Nature America, Inc. All rights reserved.

Figure 2 Top nine categories of biologic drugs in terms of US sales in 2011. (a) US sales ($ billions) of these drug categories. (b) Growth rates of the categories in 2010 and 2011. The red boxes indicate the categories showing the fastest growth rate during that period. Manufacturers of therapeutic enzymes do not break out US sales, so those sales were estimated assuming 2030% of worldwide sales were generated in the United States.

ultra-long-lasting insulin Degludec and insulin combination analog DegludecPlus, Sanofis GLP-1 analog lixisenatide and Eli Lilly/Boehringer Ingelheims (Ingelheim, Germany) long-acting insulin analog LY2605541. Among them, Degludec is the most anticipated new product in diabetes, as it has the advantage that it can last up to 40 h, which would be a great advancement over current long-acting insulin analogs13. In November 2012. FDA advisory committee voted to approve Degludec.

Growth factors 2011 marked the sixth year of continuous decline in sales of growth factors, which fell to $7.9 billion, almost half the peak sales of $14.1 billion in 2006 (Figs. 2 and 6). This sector had previously experienced major events related to safety issues and reimbursement, and is now facing new lower-priced competitors, which are likely to continue to put downward pressure on sales. Trends for Q1 and Q2 2012 show further high single-digit declines in sales of this sector. These sales

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Box 2 Five years of company rankings

Sales trends (Fig. 3) over the past five years reveal that several companies have outperformed their counterparts and growth of the sector as a whole. Since 2006, Genentech has grown its US sales by nearly $5 billion, from $7 billion to $11.8 billion, largely from expanding indication of its top-selling drug, Rituxan, Avastin and from sales of Lucentis in the large wet AMD market. Roches acquisition of Genentech in 2009 has catapulted the big pharma company to 2nd place overall in US biologic sales (before the merger, the Swiss company had US sales of only $0.5 billion for interferons). Two other companies that have seen impressive growth and movement up the rankings are Novo Nordisk and Sanofi. Novo has grown its US sales from $1.7 billion five years ago to $4.0 billion in 2011. Sanofi has shown even greater growth, moving from 7th place in 2006 to 5th place in 2011, with sales of insulin (Lantus) boosting revenues in the United States from $1.3 billion to $3.9 billion. The addition of the Genzyme franchise, with its cadre of enzyme replacement therapies, could further add to Sanofis bottom line. The story is not all of winners, however. Johnson & Johnson sales have declined since a high of $5.4 billion in 2006. Although Amgen (just) remains the company with the largest US sales of biologics, its revenues slipped from $14.2 billion in 2006 to a low of $12 billion in 2009 (they have since bounced back a little to $12.5 billion, with growth in all major product lines, countering losses with its once blockbuster Epogen (epoetin alpha)). In 2006, Amgen sold $7 billion more product than any other company; the fact that Roche is now just $0.2 billion behind in US sales reveals how much ground the Thousand Oaks biotech has lost. With several new drugs in late-stage developmenta new osteoporosis drug and a cholesterollowering drugAmgen might retain its top post in the coming years.

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Figure 3 Companies with the top sales of biologic drugs in 2011. (a) Total US sales (in $ billions) of the top 13 companies. (b) Annual growth rates of the top ten companies. Red boxes indicate companies that had biologics sales growth of >10%. Genentech comprised $11.8 billion of Roches $12.3 billion of US sales. For the purpose of this analysis, Rituxan US sales have been split equally between Genentech and Biogen Idec; Erbitux US sales were split 40/60 between Lilly and BMS.

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2012 Nature America, Inc. All rights reserved.

Lilly BMS AstraZeneca

belong to 13 brands of growth factors (12 original molecules) currently available in the United States, most falling into the category of erythropoietin-stimulating factors (ESAs) and colony-stimulating factors (CSFs). The ESA market has declined substantially over the past five years, with sales falling by another 25% in 2011, reaching $3.8 billion. The recent decline was due to the bundling of payments by the US Centers for Medicare & Medicaid Services, which has reversed the incentives for prescribing these products, from overusing to underusing. Data for 20112012 from the US Renal Data System show that intravenous iron use (which provides cost savings over ESA) as well as transfusion rates have increased, as more providers are using fewer ESAs14. This year, the FDAs approval of Affymax (Palo Alto, CA, USA)/Takedas Omontys (peginesatide), a peptide EPO mimetic, was a landmark event ending an almost two-decade-long monopoly by Amgen (Thousand Oaks, CA, USA) in this market. However, the uptake of a new ESA is compounded by the unique structure of this market, as >80% of the dialysis centers are managed by two service providers, Fresenius (Waltham, MA, USA) and DaVita (Denver). Last year, Amgen signed a seven-year Epogen sales agreement with DaVita. During the next 23 years, more ESA products could be launched in the United States, especially Roches third-generation ESA, Mircera (methoxy polyethylene glycolepoetin beta), approved since 2007 by the European Commission but held up in the United States because of a patent dispute with
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Amgen. In addition, biosimilar products of Hospira (Lake Forest, IL, USA), Teva (Tel Aviv) and Sandoz (Holzkirchen, Germany) could escalate price wars in this market, as happened in several European markets. CSF sales in the United States grew by 10%, reaching $4.0 billion in 2011. This increase was largely due to a price increase for Amgens recombinant form of granulocyte colonystimulating factor Neulasta (pegfilgrastim) with sales of $3.0 billion, following an aver-

age sales price increase of 10.2% between Q1 2011 and Q1 2012. The double-digit increase in Neulastas price was likely due to the expected launch of new cheaper CSF products, which could take a considerable share from Amgens products. In 2012, a major event related to CSF products was the FDA approval of Tevas Neutroval (tbo-filgrastim), which was expected to be approved through the new biosimilars pathway. However, Teva used the full Biologics License Application process to seek approval for this product. In some markets outside the United States, biosimilar CSFs have been highly successful, with market share as high as 80% in some European Union markets. As biosimilar CSFs are launched in the United States, it could lead to price declines and lower sales in this category. Fusion proteins The sales of this sector grew by ~6.5% in 2011, reaching $4.3 billion (Fig. 2). Ten fusion proteins are currently in the market, although the majority of these sales (~80%)
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belong to Amgens Enbrel (etanercept; a fusion protein comprising the extracellular domain of human p75 TNF-alpha receptor linked to the Fc portion of human IgG1), sales of which grew by 4.5%, driven by price increases; unit-wise its sales have declined by 12%. As an anti-TNF product, Enbrel has lagged behind in this high-growth market and has been losing new market share to Abbotts Humira. Three new fusion products were launched this year: Zaltrap, BMS Nulojix (belatacept) and Regeneron/Sanofis (Bridgewater NJ, USA) vascular endothelial growth factor trap Eylea (afilibercept). Zaltrap Regenerons third FDA-approved, drug. Zaltrap is a recombinant fusion protein that binds to VEGF-A, VEGF-B and placental growth factor, indicated for use in combination with 5-fluorouracil, leucovorin and irinotecan (Camptosar) (a regimen called FOLFIRI), for patients with metastatic colorectal cancer, who are resistant to, or have progressed following, an oxaliplatin-containing regimen. Zaltraps peak sales in this indication are expected to be in the range of $250300 million. 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). It is an engineered version of another BMS product called Orencia (abatacept), differing only by two amino acids. Nulojix is the first selective T-cell co-stimulation blocker indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. Nulojixs peak sales are expected to be ~$500 million. Cytokines In 2011, US sales of cytokines grew to $4.2 billion, largely driven by price increases (Figs. 2 and 7a). Four kinds of cytokines are currently availableinterferon (IFN)-a indicated for hepatitis C, IFN-b for multiple sclerosis (MS), IFN-g and the interleukins. IFN-b brands are the biggest sellers in the cytokines markets, constituting 79% of the total sales of this sector. In 20102011, sales of IFN-b increased by 5%, driven by 1620% price increases for all three marketed brands. IFN-b is the only top-selling category to grow by tripledigit rates from 20072011, forcing payers to dramatically increase use of various types of prescription utilization controls (e.g., prior authorization and step edits15, which require starting treatment with the most costeffective drug before moving to more costly therapies). IFN-b unit sales have been declin-

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2012 Nature America, Inc. All rights reserved.

Figure 5 Trends in US sales of recombinant hormones. (a) 2011 sales in US market for recombinant hormones ($ billions). (b) Trends in US sales show Lantus, Levemir and Novolog rising. Others, all hormones with sales of <$200 million per year.

ing because of competition from Novartiss (Basel) small-molecule Gilenya, (fingolimod) and Biogen Idecs (Cambridge, MA, USA) Tysabri (natalizumab, humanized mAb against the cell adhesion molecule a4-integrin), both indicated for MS. Future outlook for IFN-b products looks weak, as another promising small molecule nears approval, Biogen Idecs BG-12 (dimethyl fumarate), an anti-inflammatory with neuroprotective action. Blood factors Blood factors is one of the smaller markets in the biologics sector. The seven brands that make up this category generated US sales of ~$1.2 billion in 2011 (Figs. 2 and 7b). Their sales declined by 5.8% in 2011 (Figs. 3 and 8a), driven by lower sales of factor VIIa. Three blood factors make up this market: factor VIII, factor VIIa and factor IX, constituting 32%, 25% and 43% of total sales, respectively. In the pipeline are next-generation versions of factor VII and factor IX products, which have longer half-lives than previous versionsengineered with Fc fusion, albumin or pegylationand thus could reduce the frequency of injection for patients and improve their overall quality of life. Notable ones in phase 3 clinical development are Biogen Idecs Factor VII-Fc and Factor IX-Fc and CSL Behrings (King of Prussia, PA, USA) albumin-conjugated Factor IX. As these products reach the market, they could drive higher sales in this category, driven by premium pricing and increased utilization.

Therapeutic enzymes Therapeutic enzymes are ultra-orphan therapies that are indicated for a few hundred to 1,000 patients. This category has struggled in sales due to manufacturing woes and competition from newer, lower-priced therapies. For most of these products, their manufacturers do not break out the US sales, so I have provided an estimate, assuming 2530% of worldwide sales were generated in the United States. In 2011, sales of the 11 recombinant therapeutic enzymes fell to $1.1 billion, a decline of 10% over their 2010 sales (Figs. 2 and 8a). Two notable trends in this sector are the uptake of lower-priced products and launch of new branded products. Last year, sales of Shires (Basingstoke, UK) Vpriv (velaglucurase a; recombinant human glucocerebrosidase produced by gene-activation technology) more than doubled, stealing a large share from Genzymes (Cambridge, MA, USA) Cerezyme (imiglucerase; recombinant human beta-glucocerebrosidase containing a His495 Arg substitution). Vpriv is priced at a 15% discount and is the second biologic product to be indicated for type 1 Gaucher disease. This year, Pfizer/Protalixs (Carmiel, Israel) Elyeso (taliglucerase alfa) become the third product to be approved for this indication, making this market vulnerable to price wars and share gains. Elyeso is priced at a 25% discount to Cerezyme, which could lead to important cost savings for payers and patients. Elyeso is the first approved biologic to be produced using plant cells. Interestingly, the carrot cell culture system uses disposable,
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tamide). Although they are all complementary therapies, their high price ($50,000100,000) is likely to influence physicians and payers to use only the most cost-effective products. Gardasils sales in 2011 were $411 million, 24% over its 2010 sales. The higher sales were driven by its being prescribed for males. Last years US Centers for Disease Controls Advisory Committee on Immunization Practices voted in favor of expanding the routine use of Gardasil to adolescent boys. Anticoagulants The thrombolytics and anticoagulants segment is the smallest biologics market. Last year, its sales rose by 11%, reaching $395 million (Figs. 2 and 8c). This increase was due to a 26% increase in sales of Genentech/Roches Activase (alteplase, recombinant tissue plasminogen activator), which constitutes 71% of sales in this sector. In the pipeline is the next-generation version of anticoagulant, Lundbecks (Copenhagen) Desmoteplase (a recombinant tissue plasminogen activator based on a protein found in vampire bats), which lacks the lysinebinding Kringle 2 domain, is more specific for fibrin, has a longer half-life and is safer to use. Conclusions During 20092011, overall US sales of biologics grew modestly by 56%. Notably, the sales growth would have been almost double if it had not been offset by the decline in sales of blockbuster products, such as Avastin and ESAs. The growth in sales was driven by the expanding use of existing products for oncology, diabetes and autoimmune disorders and a dozen new products launched in 2011 and 2012. Oncology remains the best-selling indication for biologics and the overall pharmaceutical sector (in the United States and globally). In the United States alone, biologics for cancer treatment generated $13.2 billion in sales. High sales in oncology are due to substantial unmet needs for various cancers and the relatively high price of cancer drugs (average cost

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Figure 6 Trends in US sales of growth factors. (a) 2011 sales in US market for growth factors ($ billions). (b) Trends in US sales show Neulasta rising, Aranesp and Epogen lagging.

flexible, sterile, polyethylene bioreactors, which may be less prone to the contamination problems that have plagued this category in the past. Another new product approved in this market is Jazz Pharmaceuticals (Dublin) Erwinaze, indicated for patients with acute lymphoblastic leukemia, who have developed an allergy (hypersensitivity) to chemotherapy drugs asparaginase and pegaspargase, when they are derived from Escherichia coli. Erwinaze is an asparaginase produced in a different host system, Erwinia chrysanthemi, and is pegylated. In the long term, the therapeutic enzymes category could experience growth as more products reach the market, though this category is experiencing price wars as some indications are getting crowded. Recombinant vaccines During 2011, recombinant vaccines sector sales experienced 14% growth, reaching $860 million, driven largely by higher sales of Dendreons (Seattle) Provenge (sipuleucel-T) and Mercks (Whitehouse Station, NJ, USA) Gardasil (human papillomavirus quadrivalent (types 6, 11, 16 and 18) recombinant vaccine) (Figs. 2 and 8b). Provenge consists of autologous antigenpresenting cells stimulated ex vivo with a fusion of prostatic acid phosphatase and granulocytemacrophage colony-stimulating factor. Last
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year, Dendreon reported that Provenge sales were $228 million, a substantial increase over its 2010 sales of $48 million. However, Provenges uptake is still below expectations, as analysts had forecast that peak US sales of Provenge could reach $34 billion16. During 2012, Provenge sales for Q1 and Q2 were $161 million, which represents a slower-thanexpected uptake. Three new prostate cancer therapies have entered the market that are indirectly in competition with Provenge, including Johnson & Johnsons (New Brunswick, NJ, USA) oral small-molecule inhibitor of 17 alpha-hydroxylase/C17,20 lyase Zytiga (abiraterone); Sanofis taxoid Jevtana (cabazitaxel); and Medivations (San Francisco) small-molecule androgen antagonist Xtandi (enzalu-

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is $100,000 per year), which makes any product a blockbuster, if it is indicated for 5,000 10,000 patients17. Based on the rich pipeline of biologic candidates, 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, generating $11.2 billion in sales in 2011. More than 90% of these sales belong to anti-TNF products, indicated for rheumatoid arthritis, psoriasis and ulcerative colitis. The anti-TNF market has been growing by high single-digit rates for the past five years. This growth is driven by the expansion of indications and use of these products in chronic long-term settings. Newer pen formulations and longterm safety data have also enabled greater use of these products. Diabetes is the indication with the thirdhighest sales for biologics and the overall pharmaceutical sector (in the United States and globally). Insulin analogs for diabetes generated ~$10 billion in US sales in 2011, a growth of 16% over their 2010 sales. This is the only indication that has grown by high double-digit rates continuously for the past decade. This high sales growth is due to an epidemic of this disease, as the prevalence of diagnosed cases of diabetes in the United States has quadrupled from 5.6 million in 1980 to 20.9 million in 2010, representing an increase from 2.5% to 6.9% of the population18. An estimated 27% of people over 65 have diabetes1. So-called biobetter insulin analogs (rapid acting, long acting and mixtures) and pen formulations developed by Novo Nordisk, Lilly and Sanofi have benefited several patient groups and improved their outcomes. The high growth of biologics for diabetes has helped Novo Nordisk, Sanofi and Lilly move up the company ranks in this sector. Based on sales growth of insulin analogs and new product pipeline, it is likely that diabetes could soon overtake autoimmune disorders as the second-top-selling indication. Three common challenges to top blockbuster products are the potential launch of biobetters or biosimilars, pricing wars and reimbursement. The impact of biobetters on the insulin market has been discussed above. With the recent establishment of a US regulatory pathway for biosimilars, some of the top blockbuster products will also likely face competition from lower-priced copies. Based on trends outside US markets, biosimilars for low-risk indications (e.g., CSFs for neutro-

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penia) could gain rapid uptake, whereas biosimilars for end-of-life care, high risk or more complex indications (e.g., human growth hormone for growth deficiency or mAbs for cancer) are likely to have slower or low uptake. As more biosimilar products reach the market, the price wars are likely to escalate. Two new products for type 1 Gaucher disease, launched in 20112012, offered 15% and 25% discounts. Reimbursement is also becoming an issue across all products, as payers are changing formulary coverage of expensive biologics, passing high costs to patients, with high coinsurance19. On a positive note, several new-product launches have shown promising sales. Last year, newer biologics cumulatively generated multibillion dollar sales, adding substantial growth to the biotech sector. Products with $100-millionplus sales are Xgeva/Prolia (denosumab, a fully human mAb targeting the receptor activator of NF-kappaB ligand, RANK-L), Stelara, Eylea, Yervoy (human mAb agonist of CTLA-4), Victoza and Provenge. Some of these products and other recent launches (e.g., Adcetris, Zaltrap and Perjeta) could drive up the future sales of the biotech sector.
AcknowledgementS SA thanks American Society of Clinical Oncology (ASCO), American College of Rheumatology (ACR), American Association of Liver Diseases (AASLD), American Heart Association (AHA), American Society of Hematology (ASH) and Biotechnology Industry Association (BIO) for providing support for this article.
1. IMS Health Top-Line Market Data. <http://www. imshealth.com/portal/site/ims> 2. Aggarwal, S. Whats fueling the biotech engine-20092010. Nat. Biotechnol. 28, 11651171 (2010). 3. Aggarwal, S. Whats fueling the biotech engine2008. Nat. Biotechnol. 27, 987993 (2009).

4. Aggarwal, S. Whats fueling the biotech engine2010 to 2011. Nat. Biotechnol. 29, 10831089 (2011). 5. Hamlin, P.A. Is maintenance rituximab now ready for PRIMA-time? Curr. Oncol. Rep. 12, 355357 (2010). 6. Garber, K. Pfizers JAK inhibitor sails through phase 3 in rheumatoid arthritis. Nat. Biotechnol. 29, 467468 (2011). 7. Sandborn, W.J. et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367, 616624 (2012). 8. van Vollenhoven, R.F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367, 508519 (2012). 9. Helwick, C. Bevacizumab beyond progression prolongs survival in metastatic colorectal cancer. The ASCO Post 3 (15 July 2012). 10. Heitz, F. et al. Bevacizumab in the treatment of ovarian cancer. Adv. Ther. 29, 723735 (2012). 11. Bach, P.B., Saltz, L.B. and Wittes, R.E., In cancer care, costs matters. NY Times, 14 October 2012 12. de Claro, R.A. et al. U.S. Food and Drug Administration approval summary: Brentuximab Vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large cell lymphoma. Clin. Cancer Res. 18, 58455849 (2012). 13. Zinman, B. et al. Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial. Lancet 377, 924931 (2011). 14. Collins, A.J. ESRD Payment Policy Changes: The New Bundled Dialysis Prospective Payment System in the United States (US Renal Data System, 2012). <http:// www.usrds.org/2012/pres/USDialysisBundle_impact_ NKFCM2012.pdf> 15. Aggarwal, S. Access, Uptake and Utilization Management of Multiple Sclerosis Products in the United States. Abstract PND72, presented at15th Annual European Congress, November 37,2012, Berlin, Germany. 16. Hayes, E. Dendreon readies for next Provenge hurdles: supply and reimbursement. The Pink Sheet Daily 71 <http://www.elsevierbi.com/publications/the-pinksheet/72/018/dendreon-readies-for-next-provengehurdles-supply-and-reimbursement> (3 May 2010). 17. Aggarwal, S. Targeted cancer therapies. Nat. Rev. Drug Discov. 9, 427428 (2010). 18. Polonsky, K.S. The past 200 years in diabetes. N. Engl. J. Med. 367, 13321340 (2012). 19. Aggarwal, S. Impact of 20092011 global health care reforms on pricing, access and health outcomes strategy. Podium Presentation UT2 presented at International Society for Pharmacoeconomics and Outcomes Research 17th Annual International Meeting, June 26, 2012, Washington, DC, USA.

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