Biosimilars: 10 Drugs to Watch

The world’s largest two markets for prescription medicines remain a study in contrasts: The European Medicines Agency authorizes 11 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.

Those guidances, released last year, left numerous questions unanswered: How similar should the near-copies be to their innovator drugs? How should drugmakers demonstrate the safety of their products? How should interchangeability of biosimilars to innovator products be determined? How should biosimilars be named and labeled? Biopharma companies are closely watching what FDA does since patents for 12 blockbuster biologic compounds generating a combined $67 billion in sales will expire by 2020, according to the Generics and 

Biosimilars Initiative. Biopharma companies don’t want to be left behind as the biosimilar segment grows—from $172 million in 2010 to an estimated $3.927 billion by 2017, according to Frost & Sullivan.

EMA defines biosimilars as “similar to a biological medicine that has already been authorized, the so-called reference medicinal product.” FDA has proposed using slightly stricter wording, declaring that, in order to be considered a biosimilar, the biological product must be “highly similar to the reference product notwithstanding minor differences in clinically inactive components.” By minor differences, the agency states that there should be no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

As reported in this space last year, “EMA’s development of solid guidelines almost a decade ago followed by specific rules for different drug classes helps explain why Europe is much further along than the U.S. in bringing biosimilars to market.” Little has changed since then.

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 2012 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:

• Dr. Reddy’s Laboratories: Cresp® launched 2010 in India as that country’s only darbopoetin alfa of any kind, and as world’s first generic darbopoetin alfa.
• 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.

2012 sales: $2.040 billion (Amgen)

Patent status: Patent set to expire 2016 in EU; 2024 in U.S.

Enbrel (etanercept)

Drug developers:

• Avesthagen: Avent™ in preclinical studies as of 2012
• BioXpress Therapeutics: Biosimilar in active development
• Cipla: Launches biosimilar in India on April 17, at a price of Rs. 6,150 ($113.43), 30% less than the innovator product.
• Hanwha Chemical: HD203 “scheduled for launch,” company states on its website without including a date, following submission for marketing approval to South Korea’s Korea Ministry of Food and Drug Safety following completion of Phase I and Phase III trials. Hanwha has said it will seek a partner to commercialize HD203 and a biosimilar for Herceptin (trastuzumab).
• LG Life Sciences: LBEC0101 completed Phase I trial in South Korea
• Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea
• Protalix Biotherapeutics: PRX-106 in preclinical studies
• Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China

Recently discontinued effort: Merck & Co. and Hanwha Chemical: Hanwha disclosed December 18, 2012, that Merck terminated agreement to develop and manufacture the biosimilar MK-8953, now called HD203, as well as market it in all countries except South Korea and Turkey, an up to $720 million deal signed June 2011.¹

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

2012 sales: $7.963 billion (includes $4.236 billion Amgen + $3.737 billion Pfizer). Amgen markets Enbrel in U.S. and Canada under an agreement with Pfizer set to expire October 31, 2013

Patent status: Patents set to expire in EU in 2015; in U.S., 2019, 2023, 2028, and 2029.

Epogen® / Procrit® / Eprex / Erypo (epoetin alfa)

Drug developers:

• Hexal: Epoetin alfa Hexal marketed in EU, where it was authorized August 2007 for anemia, cancer and chronic kidney failure
• Hospira: Retacrit® marketed in EU, where it was authorized in December 2007 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. 
• Medice: Abseamed® marketed in EU, where it was authorized August 2007 for anemia, cancer, and chronic kidney failure
• 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.

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

2012 sales: $2.267 billion, including $1.941 billion for Epogen (Amgen), and $326 million combined for Procrit / Eprex / Erypo (Johnson & Johnson) Amgen also generated

Patent status: Patent set to expire 2015 in U.S.; expired 2004 in EU.

Genotropin (Somatropin or somatotropin)

Drug developers:

• BioPartners: Valtropin® marketed in EU, where it was authorized April 2006, 12 days after Omnitrope, for pituitary dwarfism and Turner syndrome; authorization withdrawn voluntarily “for commercial reasons” in October 2011, and withdrawn formally in May 2012.
• Sandoz: Omnitrope® marketed in EU, where it was authorized April 2006 for pituitary dwarfism, Prader-Willi syndrome, and Turner syndrome; the first biosimilar authorized by the European Medicines Agency. In U.K., was the first biosimilar recommended for approval by the National Institute for Health and Clinical Excellence in 2010. In Japan, launched October 2009 as that nation’s first approved biosimilar

Nature and indication: Peptide human growth hormone for children with growth failure due to growth hormone deficiency (GHD), Prader-Willi syndrome, small for gestational age, Turner syndrome, and idiopathic short stature; and for adults with either adult onset or childhood onset GHD. Pursuing FDA approval since 2009 for additional indication, Replacement of human growth hormone deficiency (Mark VII multidose disposable device); received two complete response letters. “We are working to address the FDA's requests for additional information,” Pfizer stated in its 2012 Financial Report.

2012 sales: $832 million (Pfizer)

Patent status: Patents expired 2008 and April 16, 2013 in U.S.

Herceptin (trastuzumab)

Drug developers:

• Amgen, Synthon, and Watson (now Actavis): Global licensing agreement announced July 18, 2012, for clinical development and testing of biosimilar. Deal followed publication March 2, 2012, of Phase I trial results showing bioequivalence between Synthon’s biosimilar and Herceptin
• BioXpress: Biosimilar in active development
• Hanwha Chemical: Biosimilar in development. Hanwha has said it is seeking a partner to commercialize Herceptin and HD203, a biosimilar for Enbrel
• Hospira: Biosimilar in active development.
• Pfizer: PF-05280014 completed Phase I REFLECTIONS B327-01 trial as of December 2012, to study the safety and pharmacokinetics of the biosimilar compared to Herceptin. The study yielded “positive data,” hence the company “is exploring plans to go into Phase III this year, Mikael Dolsten, president of Pfizer’s Worldwide Research & Development unit, said on the Q4 2012 earnings conference call January 29.
• PlantForm: Clinical trials in humans expected to begin in 2014. Biosimilar expected to be launched, “in partnership with a pharmaceutical company,” in world markets in 2016
• Stada Arzneimittel: Joined with Gedeon Richter in announcing plans August 2011 to collaborate on biosimilars for trastuzumab and rituximab. Richter agreed to buy from Stada trastuzumab for a “low single-digit million Euros figure,” they announce.

Nature and indication: Monoclonal antibody; Human epidural receptor 2 (neu) receptor antagonist for aggressive HER positive metastatic and adjuvant breast cancer, for aggressive HER positive metastatic stomach or gastroesophageal junction cancer.

2012 sales: $6.317 billion (CHF 5.889 billion) (Roche)²

Patent status: Patents set to expire July 2014 in Europe, and June 2019 in the U.S.

Humira (Adalimumab)

Drug developers:

• AET BioTech and BioXpress: Biosimilar being co-developed under agreement announced October 25, 2012; companies will be jointly responsible for development, registration, and manufacture of the biosimilar, based on BioXpress technology. AET BioTech will provide further investment in the biosimilar based on committed long-term financing, and oversee any future commercialization of the product.
• Amgen: Biosimilar in active development
• Boehringer Ingelheim: BI695501 completed Phase I trial in New Zealand, studying the biosimilar’s safety and pharmacokinetics compared to Humira (adalimumab) in October 2012.
• Fujifilm and Kyowa Hakko Kirin: Companies announce 50–50 joint venture, Fujifilm Kyowa Kirin Biologics, to develop a biosimilar version of Adalimumab for rheumatoid arthritis. The venture is proceeding with preparations to begin clinical trials in Europe in the first half of 2013, the companies said October 24, 2012.

Nature and indication: Anti-TNF-α monoclonal antibody for moderate to severe rheumatoid arthritis, moderate to severe chronic plaque psoriasis, moderate to severe Crohn’s disease; moderate to severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate to severe polyarticular juvenile idiopathic arthritis

2012 sales: $9.265 billion (AbbVie)³

Patent status: Patent set to expire 2016 in U.S.; 2018 in EU.

Neulasta (pegfilgrastim)

Drug developers:

• Hospira: Biosimilar in development.
• Merck & Co.: MK-6302 said to be in clinical development as of 2011 for neutropenia caused by cancer chemotherapy; no further announcement since then on ‘6302, acquired through acquisition of Insmed in 2009
• Teva: Neugranin launch delayed in 2011, when company reached settlement of litigation with Amgen in which it agreed not to sell Neugranin until November 10, 2013 unless it first obtains a final court decision that Amgen patents are not infringed by the biosimilar.
• Teva: Lipefilgrastin (XM22) meets primary endpoint in Phase III clinical trial of reducing the duration of severe neutropenia, in a study designed to evaluate the efficacy and safety of lipegfilgrastim compared to pegfilgrastim, the company said June 6, 2011.

Nature and indication: Leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia

2012 sales: $4.092 billion

Patent status: Patents set to expire August 2015 in EU; October 2015 in U.S.

Neupogen (filgrastim)

Drug developers:

• Biocon and Celgene: Nufil marketed in India by Biocon; in active development for EU by joint venture
• ctArzneimittel: Biograstim® marketed in EU, where it was authorized September 2008 for cancer, hematopoietic stem cell transplantation, and neutropenia
• Dr. Reddy’s Laboratories: Grafeel marketed in India
• Hexal: Filgrastim Hexal® marketed in EU, where it was authorized February 2009 for cancer, hematopoietic stem cell transplantation, and neutropenia
• Hospira: Nivestim™ marketed in EU, where it was authorized June 2010 for cancer, hematopoietic stem cell transplantation, and neutropenia
• Intas/Apotex: Neukine in Phase III development
• Merck & Co.: MK-4214 in Phase III clinical development; acquired through acquisition of Insmed in 2009
• Ratiopharm: Ratiograstim® marketed in EU, where it was authorized September 2009 for cancer, hematopoietic stem cell transplantation, and neutropenia. Authorization withdrawn voluntarily March 2011, followed two months later by formal European Commission withdrawal.
• Sandoz: Zarzio® marketed in EU, where it was authorized February 2009 for cancer, hematopoietic stem cell transplantation, and neutropenia In U.S., recruiting patients as of January for a noninterventional, long-term safety data collection of the biosimilar and Filgrastim Hexal® in stem cell donors (NCT01766934)
• Teva: Tevagrastim® marketed in EU, where it was authorized September 2008 for cancer, hematopoietic stem cell transplantation, and neutropenia

Nature and indication: Granulocyte colony-stimulating factor (G-CSF) for neutropenia caused by the drugs used to treat cancer

2012 sales: $1.260 billion (Amgen)

Patent status: Patent set to expire December 2013 in U.S.; Patent expired 2006 in EU.

Remicade (infliximab)

Drug developers:

• Amgen: Biosimilar in active development
• BioXpress: Biosimilar in active development
• Celltrion: Ramsima™ (formerly CT-P13) authorized for marketing in Korea on July 20, 2012, for rheumatoid arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and psoriasis. Applied for marketing authorization in EU
• Hospira: Biosimilar in active development.

Nature and indication: Tumor necrosis factor (TNF) blocker for moderately to severely active rheumatoid arthritis in adults, in combination with methotrexate; Crohn's disease in children six years and older, and adults who have not responded well to other medicines; rheumatoid arthritis; ankylosing spondylitis; psoriatic arthritis; chronic, severe, extensive, and/or disabling plaque psoriasis in adults; moderately to severely active ulcerative colitis in children six years and older and adults that have not responded well to other medicines.

2012 sales: $8.215 billion ($6.139 billion Johnson & Johnson + $2.076 billion Merck & Co.)

Patent status: Patents set to expire 2014 in Europe, and 2018 in U.S.

Rituxan / MabThera (rituximab)

Drug developers:

• Amgen: Biosimilar in active development
• BioXpress: Biosimilar in active development
• Boehringer Ingelheim: BI695500 in Phase III development in U.S., EU, Brazil, Guatemala, Russia, Norway, Ukraine, Argentina, Peru, New Zealand. U.S. study recruiting participants as of April 17, according to ClinicalTrials.gov (NCT01682512)
• Celltrion and Hospira: Conducting Phase I trial in South Korea of CT-P10 for RA and another Phase I trial for lymphoma.
• Dr. Reddy’s Laboratory: Reditux® marketed in Bolivia, Chile, India, and Peru
• iBio: Announces October 5, 2011, that it produces rituximab in nontransgenic green plants. More recent announcements, however, focus on the company’s technologies for developing biosimilar and proprietary drugs. On April 26, 2012, announces results of ongoing tests showing that its immunomodulator molecule lichenase (LicKM) enhances vaccine antigens when produced as fusions to LicKM. iBio said it will offer commercial collaborations and product licenses to the immunomodulator, dubbed iBioModulator™, which last month was awarded U.S. Patent No. 8,404,252. The iBioModulator has been shown in animal models to increase the strength and extend the duration of immune response to a vaccine antigen.
• Merck: MK8808 in Phase I development for EU, with trial in Belarus
• Pfizer: PF-05280586 set this year to complete a Phase II trial launched March 2012 comparing the biosimilar to Rituxan/MabThera. “This year, we expect data,” Mikael Dolsten, president of Pfizer’s Worldwide Research & Development unit, said on the Q4 2012 earnings conference call January 29.
• Probiomed: Kikuzubam® marketed in Bolivia, Chile, Mexico, and Peru
• Roche: CEO Severin Schwan was quoted in March as pushing back his company’s anticipated launch of a rituximab biosimilar beyond the 2016 date he had earlier cited in The Wall Street Journal, until the end of this decade.
• Sandoz: GP2013 in Phase I/II trial for rheumatoid arthritis and non-Hodgkin’s lymphoma, and a Phase III trial for advanced folicular lymphoma. As of last year, the biosimilar was in Phase II trials in Argentina, Austria, Brazil, France, Germany, India, Italy, Spain, and Turkey.
• Stada Arzneimittel: Joined with Gedeon Richter in announcing plans August 2011 to collaborate on biosimilars for rituximab and trastuzumab. Stada receives nonexclusive rights to sell Richter-produced rituximab in Europe and the Commonwealth of Independent States, excluding Russia. In addition to an undisclosed payment to Richter, Stada also agrees to pay Richter based on progress of the development of rituximab to a “low double-digit million Euros”

Recently discontinued efforts:

• Teva and Lonza: End planned 544-patient, Phase III clinical trial of TLO11, saying they wanted input from regulators on designing the trial program (October 2012). On April 5, Lonza issues statement denying news reports that it will end its biosimilar joint venture with Teva⁴
• Samsung Biologics: Venture between Samsung and Quintiles halts development of SAIT101, in October 2012, reportedly due to uncertainty over biosimilar regulation in the U.S.

Nature and indication: Chimeric mouse-human monoclonal antibody, for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis

2012 sales: $7.190 billion (CHF 6.707 billion) (Roche)⁵

Patent status: Patents set to expire later this year in EU, and 2018 in U.S.

Among other drugs for which biosimilar efforts have been announced in recent months:

• Avastin (Bevacizumab): Amgen is developing a biosimilar to the breast cancer drug, while Fujifilm and Kyowa Hakko Kirin on October 24, 2012, announce 50–50 joint venture, Fujifilm Kyowa Kirin Biologics, to develop a biosimilar version of Avastin (Roche / Genentech) for cancer indications
• Lispro: Biocon and Mylan announed a strategic collaboration February 14 to develop a biosimilar to the generic version of insulin analog Humalog (Eli Lilly)
• Glargine: Biocon and Mylan on February 14 announced a strategic collaboration to develop a biosimilar to the insulin analog Lantus (Sanofi)

Notes:
¹ 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 Sales figures converted to USD via XE (www.xe.com) on April 18, 2013
³ Company spun out January 2, 2013, from Abbott Laboratories, whose portfolio included Humira during 2012. AbbVie has promised to fight off biosimilar challengers through a vigorous defense of what it says are some 200 patents covering Humira.
⁴ Those news reports follow an interview of Lonza CEO Richard Ridinger by the Swiss newspaper Finanz und Wirtschaft, in which he says that “a joint venture team is reassessing at the moment whether our assumptions from 2009 are still correct” and questions whether the joint venture with Teva will continue to exist.
⁵ Sales figures converted to USD via XE (www.xe.com) on April 18, 2013. Q4 figures not reported for each drug by Roche, but derived by subtracting January-September sales, which are reported by the company in its third-quarter results, from full-year sales.

Fuente: GEN

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