Biosimilars: 11 Drugs to Watch

If imitation is the sincerest form of flattery, these innovator drugs should be blushing.

May 9 saw the latest estimate of the potential size of the market for biosimilar drugs—$167 billion by 2017, according to Companiesandmarkets.com. It’s an exponential leap from the estimate made earlier this year by Frost & Sullivan that biosimilar sales will reach $23 billion in 2019, up from what it estimated as $1.2 billion in 2013 sales.
The past few years has seen a flurry of worldwide activity by drug developers in creating, winning regulatory approvals for, then launching biosimilars. The operative word here is “worldwide”—Europe remains miles ahead of the U.S. The European Medicines Agency authorizes 18 biosimilar drugs for market in the nations comprising the EU. Meanwhile in the U.S., the FDA continues to ponder draft guidances for how the agency will evaluate biosimilars.
FDA insists it is moving ahead with careful review of new regulations. FDA’s Center for Drug Evaluation and Research (CDER) earlier this year published an agenda for new and revised draft guidances that included several new topics the agency said will be addressed: clinical pharmacology data to support a demonstration of biosimilarity to a reference product; considerations in demonstrating interchangeability to a reference product; labeling for biosimilar biological products; and reference product exclusivity for biological products. CDER also included a biosimilar topic published in previous agendas, additional questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009.
One reflection of increased activity: This year’s list reports on 11 biosimilars to watch, as Avastin (bevacizumab) and Erbitux (cetuximab) have been added to reflect an uptick in announcements or disclosures about biosimilar versions of those drugs since 2013, while Genotropin (somatropin or somatotropin) has been removed for not generating as much activity.
Following is a list of 11 drugs for which, over the past year, biosimilars have been launched to market somewhere in the world, were in clinical development, or whose development was ended. Drugs are listed by original brand name (generic name), followed by a list of drug developers with a brief summary of the status of their biosimilar, and its name where known; the nature of the drug and its indication; its 2013 sales (and the original drug’s maker or makers); and the drug’s patent status in the U.S. and EU.
Aranesp (darbepoetin alfa)
Drug developers:
- Avesthagen Pharma (APAG): The spinout of Avesthagen said November 19, 2013, that it signed a distribution agreement granting Greek-based Elpen Pharmaceutical rights to distribute APAG’s biosimilar darbepoetin alfa (Avdesp) in seven European Union countries (Bulgaria, Croatia, Cyprus, Greece, Romania, Slovakia, and Slovenia) and six non-EU territories (Albania, Bosnia, Former Yugoslav Republic of Macedonia, Kosovo, Montenegro, and Serbia). Avdesp is one of eight biosimilars marketed by APAG.
- Dr. Reddy’s Laboratories: Cresp launched 2010 in India as that country’s only darbopoetin alfa of any kind, and as the world’s first generic darbopoetin alfa
- Hospira: Retacrit marketed in EU, where it was authorized in December2007 for anemia associated with chronic renal failure or other kidney problems, adults receiving chemotherapy for some cancers. Also indicated to increase the amount of blood patients with moderate anemia can self-donate before surgery, and to reduce the need for blood transfusions in patients with moderate anemia about to undergo major bone surgery. In U.S., Phase III trial launched last year.
- Merck: MK-2578 development halted in 2010
- Stada: Silapo marketed in EU, where it was authorized December 2007 for anemia that is causing symptoms in patients with chronic renal failure; anemia in adults receiving chemotherapy to treat certain types of cancer and to reduce the need for blood transfusions; and to increase the amount of blood patients with moderate anemia can self-donate before surgery.
Nature and indication: Erythropoiesis-stimulating agent (ESA) for anemia due to chronic kidney disease (CKD) in patients on dialysis and patients not on dialysis; the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
2013 sales: $1.911 billion, down 6% from 2012 (Amgen)
Patent status: Patent set to expire 2016 in EU; 2024 in U.S.
Avastin (bevacizumab)
Drug developers:
- Amgen: Biosimilar in development, with pivotal trial launched in 2013, the company stated in a letter to shareholders accompanying its Form 10-K for last year. The biosimilar is one of four for oncology indications that Amgen is developing in collaboration with Actavis.
- Biocad: Biosimilar in late-stage clinical study
- BioXpress Therapeutics: Biosimilar in pipeline
- Fujifilm and Kyowa Hakko Kirin: Announced a 50–50 joint venture, Fujifilm Kyowa Kirin Biologics, on October 24, 2012, to develop a biosimilar version of Avastin (Roche / Genentech) for cancer indications
- Oncobiologics and Viropro: Biosimilar in development; one of six monoclonal antibody biosimilars on which the companies agreed to collaborate under an agreement announced February 25, 2013. Viropro has rights to manufacture the six products being developed by Oncobiologics, with Viropro holding exclusive commercialization rights to the six for Malaysia, while both companies will co-manage Viropro’s Penang, Malaysia Alpha Biologics biomanufacturing subsidiary.
Nature and indication: Vascular endothelial growth factor-specific angiogenesis inhibitor indicated for the treatment of: Metastatic colorectal cancer, with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment; Metastatic colorectal cancer, with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen; Non-squamous non-small cell lung cancer, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease; Glioblastoma, as a single agent for adult patients with progressive disease following prior therapy; Metastatic renal cell carcinoma with interferon alfa
2013 sales: $7.106 billion (CHF 6.254 billion) (Roche), up 8.5% from 2012
Patent status: Patent set to expire 2018 in Europe; 2019 in U.S.
Enbrel (etanercept)
Drug developers:
- Avesthagen: Avent in preclinical studies as of 2012; received patent in India, 2010
- BioXpress Therapeutics: Biosimilar in pipeline
- Cipla: Marketed in India following launch last year as that country’s first etanercept biosimilar
- CP Guojian Pharmaceutical: Markets biosimilar as Yisaipu in China and Etanar in Colombia
- Hanwha Chemical: HD203 marketed in South Korea following approval in 2013.¹
- LG Life Sciences: LBEC0101 completed two Phase I studies, both comparison of safety and pharmacokinetics to Enbrel; one was completed as of 2013 (NCT01725620); the other, as of 2011 (NCT01145950).
- Momenta: M923, company’s lead biosimilar program, predicted to be a near-copy of either Enbrel or Humira;² company has not confirmed which, but has said it plans a regulatory filing later this year²
- Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea; completed a Phase I trial among 24 healthy subjects in South Korea, and a Phase I/II trial that enrolled 18 patients with rheumatoid arthritis in Taiwan
- Protalix Biotherapeutics: PRX-106 in preclinical studies
- Shanghai CP Goujian Pharmaceutical: Yisaipu, marketed in China; Etanar, marketed in Colombia
Nature and indication: Tumor necrosis factor (TNF) blocker for rheumatoid arthritis, polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged two years or older; psoriatic arthritis; ankylosing spondylitis; and plaque psoriasis
2013 sales: $8.760 billion (including $4.551 billion Amgen + $3.774 billion Pfizer + $0.435 billion Takeda)³
Patent status: Patents set to expire February 2015 in EU; U.S. patents set to expire 2028 and 2029
Epogen / Procrit / Eprex / Erypo (epoetin alfa)
Drug developers:
- Biocon: Erypro Safe pre-filled syringes marketed in India following 2008 launch
- Claris Lifesciences: Epotin marketed in India
- Emcure: Epofer marketed in India
- Hexal: Epoetin alfa Hexal marketed in EU, where it was authorized August 2007 for anemia, cancer and chronic kidney failure
- Intas Biopharmaceuticals: Epofit/Erykine marketed in India, where it was launched 2005
- Medice: Abseamed marketed in EU, where it was authorized August 2007 for anemia, cancer, and chronic kidney failure
- Ranbaxy: Ceriton marketed in India
- Reliance Life Sciences: Relipoietin marketed in India, where it was launched 2008
- Sandoz: Binocrit marketed in EU, where it was authorized August 2007 for anemia and chronic kidney. In U.S., the company said October 25, 2012, that it has started patient enrolment in a Phase III clinical trial, comparing safety and efficacy of biosimilar with reference product Epogen/Procrit in anemia associated with chronic kidney disease.
- Wockhardt: Wepox marketed in India, where it was launched 2001
Nature and indication: Erythropoiesis-stimulating agent for anemia due to chronic kidney disease in patients on dialysis and not on dialysis; due to Zidovudine in HIV-infected patients; and due to effects of concomitant myelosuppressive chemotherapy, where upon initiation, there is a minimum of two additional months of planned chemotherapy. Also, for reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery
2013 sales: $3.317 billion (including $1.953 billion for Epogen [Amgen], and $1.364 million combined for Procrit / Eprex [Johnson & Johnson], down 2.5% from 2012
Patent status: Patent set to expire 2015 in U.S.; expired 2004 in EU
Erbitux (cetuximab)
Drug developers:
- Amgen: Developing a biosimilar in collaboration with Actavis
- BioXpress Therapeutics: Biosimilar in pipeline
- Oncobiologics and Viropro: Biosimilar in development; one of six monoclonal antibody biosimilars on which the companies agreed to collaborate under an agreement announced February 25, 2013. Viropro has rights to manufacture the six products being developed by Oncobiologics, with Viropro holding exclusive commercialization rights to the six for Malaysia, while both companies will co-manage Viropro’s Penang, Malaysia Alpha Biologics biomanufacturing subsidiary.
Nature and indication: Epidermal growth factor receptor (EGFR) antagonist indicated for locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy; recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU; recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy; KRAS mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer in combination with FOLFIRI for first-line treatment, in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, or as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan
2013 sales: $2.283 billion ($1.222 billion [€882 million] Merck KGaA + $696 million Bristol-Myers Squibb [BMS] + $373.7 million Eli Lilly [ImClone subsidiary]), down 1.7% from 2012
Patent status: Patent set to expire in Europe June 29, 2014; data exclusivity ends 2016 in U.S. As a biologic there is no patent that specifically claims the composition of matter of cetuximab.

Notes:
¹ HD203 was co-developed by Merck & Co., which had planned to develop and manufacture the biosimilar (then called MK-8953) as well as market it in all countries except South Korea and Turkey, in an up-to-$720 million deal signed June 2011. Hanwha disclosed December 18, 2012, that Merck terminated that agreement. Merck has said it remains committed to developing biosimilars, citing its February 20 announcement with Samsung Bioepis of an agreement to “develop and commercialize multiple pre-specified and undisclosed biosimilar candidates.”
² In the May 6 press release announcing its first quarter 2014 results, Momenta added information on other unidentified biosimilar programs, saying it was “advancing toward multiple biosimilars development milestones,” and “expect(s) to complete the Part A study of our M402 program in the next several months, with data likely available in the second half of 2014."
³ Pfizer does not furnish individual sales figures for Enbrel in the U.S. or Canada, but combined those sales through October 31, 2013, in a category called “Alliance revenues” which also includes sales of Enbrel (in the U.S. and Canada through October 31, 2013), as well as Aricept, Eliquis, Rebif, and Spiriva.
⁴ The two possibilities were laid out in an April 29, 2014, article in Seeking Alpha by “Signal to Noise,” an anonymous contributor who cites “22 years of experience as an investment analyst and a portfolio manager running institutional money.” See http://seekingalpha.com/article/2172193-momenta-pharmaceuticals-has-value-in-the-sum-of-the-drugs
⁵ Amgen attributed the increase to a $155 million order from the U.S. government during the third quarter of 2013
⁶ Biogen Idec figure includes sales from a next-generation version of Rituxan, Gazyva (obinutuzumab), but those are likely minimal since Gazyva launched in November 2013