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Biosimilars

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Cedric Burg

on 30 October 2014

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Transcript of Biosimilars

Biosimilars
Hard road ahead
Main Idea
Biosimilars, follow-on biologics, subsequent entry biologics, etc... Development of generic alternatives to biological therapies
Companies
Legislation
EMEA
Drugs
FSH
Follitropin Alfa and Beta
Original drug: Gonal-f®, from Merck-Serono, Puregon® (Schering Plough, MSD), Follistim® (Schering Plough, MSD)
Indication: fertility treatments for ovulation induction (OI) and in vitro fertilization (IVF).
Finox Biotech. submitted Afolia to EMA in December 2012. US Phase III trial in submission process. Bemfola approved in EMA in MAr 14
http://clinicaltrials.gov/ct2/show/NCT01687712
11 sites/1106 patients
Timelines May 2013-March 2016. Primary endpoint July 2014
US only
United States, Florida
FL Fertility Institution Not yet recruiting
Tampa, Florida, United States, 33759
Contact: Gayle Cameron 727-724-9730 gaylec@xxresearch.com
United States, Illinois
Fertility Centers of Illinois Not yet recruiting
Chicago, Illinois, United States, 60610
Contact: Sue Jausalitis 312-222-8200 Sue.Jausalitis@integramed.com
United States, Maryland
Shady Grove Not yet recruiting
Rockville, Maryland, United States, 20850
Contact: Tasha Newsome 866-750-4640 tasha.newsome@integramed.com
United States, New York
New York University School of Medicine Not yet recruiting
New York, New York, United States, 10016
Contact: David Keefe, MD 212-263-0774 david.keefe@nyumc.org
United States, Ohio
Institute for Reproductive Health Not yet recruiting
Cincinnati, Ohio, United States, 45209
Contact: Michael Scheiber 513-924-5550 scheibermd@gmail.com
United States, Pennsylvania
Mainline Fertility Center Not yet recruiting
Bryn Mawr, Pennsylvania, United States, 19010
Contact: Eileen Davies 484-380-4861 daviese@mainlinefertility.com
United States, Tennessee
Fertility Associates of Memphis Not yet recruiting
Memphis, Tennessee, United States, 38120
Contact: William Kutteh 901-747-2229 wkutteh@fertilitymemphis.com
United States, Texas
Texas Fertility Center Not yet recruiting
Austin, Texas, United States, 78731
Contact: Tamara Minter 512-451-7432 tamara@txfertility.com
Center for Assisted Reproduction Not yet recruiting
Bedford, Texas, United States, 75022
Contact: Lee Ann Hoffman 817-924-1572 LeeAnnH@embryo.net
Infertility Texas Not yet recruiting
Webster, Texas, United States, 77598
Contact: Marianne Fisher 281-557-3084 MFisher@infertilitytexas.com
United States, Virginia
Jones Institute for Reproductive Medicine Not yet recruiting
Norfolk, Virginia, United States, 23507
Contact: Barbara Ross 757-446-8929 RossBK@EVMS.EDU
Teva (BioGenerix AG). Phase III trial in Europe started with XM17. Ovaleap Approved in by EMA in Sept 13
Glycotope GmBH has glyco-optimised FSH in phase II in Europe (FSH-GEX).
http://clinicaltrials.gov/show/NCT01794208

240 patients, sites at least in Germany and Hungary
Timelines annouces as Jan 2013 to April 2014, but no updated infor in CT.gov
http://www.glycotope.com/pipeline
patient forum: http://forums.fertilitycommunity.com/forum/infertility/general-infertility-support/infertility-support/infertility-support-forum/67340-afolia-clinical-trial
Recruitment to start in September
http://www.finox.ch/pages/en/Corporate.html
LG life Science has Follitrope in market in Asia since 2006. Does not look like they intend to expand for now
https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-017674-20/BE
Herceptin® (from agreement with Synthon), Avastin®, Rituxan/MabThera®, and Erbitux®, recombinant follicle stimulating hormone (rFSH) from Itero Biopharmaceuticals, Inc.’s
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 (Nivestim) of Neugranin approved in EU since 2010.
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:
Lonquex 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. Approved in EU in August 2013.
Sandoz:
Phase III trial for pegfilgrastim (LA-EP2006) initiated in 2012. Currently being filed
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
Remicade (infliximab)

Drug developers:

Amgen: Biosimilar in active development
BioXpress: Biosimilar in active development
Celltrion: (Remsima®) and Hospira: (inflectra®) (formerly CT-P13) authorized for marketing in Korea on July 20, 2012, for rheumatoid arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and psoriasis. Approved in EU in 2013
HISUN Pharmaceuticals Co. in partnership with Catalent
Pfizer (PF-06438179)
Epirus: BOW015 In development, manufactured by Orygen Biotecnologia in Brazil, agreement with Ranbaxy
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)
Patents
Trials
Phase I: 174 patients in 2012-13 in Korea
(NCT01571206)
Phase III: 606 patients in 100 sites
The authors wish to thank the patients and study personnel who made this trial possible and the PLANETRA study investigators—Bosnia: Mulic Bacic S; Bulgaria: Bichovska D, Kadinov V, Oparanov B, Rashkov R, Toncheva A; Chile: Aguirre V, Arriagada Herrera M, Barria Negron L, Goecke Sariego I; Colombia: Chalem M, Diaz Cortez M, Otero Escalante WJ, Ruiz Santacruz O, Tobias Arteaga E; Italy: Bianchi G, Cutolo M, Salvarani C; Jordan: Alawneh K; Latvia: Andersone D, Saleniece S, Saulite-Kandevica D; Lithuania: Baranauskaite A, Bukauskiene L, Kausiene R, Smilgiene V, Stropuviene S; Mexico: Abud-Mendoza C, Araiza R, Cardona Cabrera R, Cons Molina F, Diaz Jimenez A, Morales-Torres J, Pacheco-Tena C, Xibille D; Peru: Calvo A, Castaneda Jimenez M, Chalouhi El-Khouri E, Chavez Corrales J, Vidal Neira L; Philippines: Amante EJ, Baes R, Eullaran R, Lanzon A, Lucero A Jr, Navarra S, Salido E, Tan P; Poland: Brzezicki J, Brzosko M, Daniluk S, Jaworski J, Klimiuk P, Krogulek M, Racewicz A, Ruzga Z, Wiland P; Portugal: Vaz Patto J; Romania: Bojinca VC, Chicea LM, Cristei D, Ianuli-Arvunescu MA, Motoc D, Pavel M, Rednic S; Slovakia: Jancovic R, Krpciar M, Zlnay D; Spain: Blanco Garcia F, Fernández-Nebró A, Gómez Centeno A, Martín-Mola E, Ucar Angulo E; UK: Adebajo A, Byrne P; Ukraine: Amosova K, Dzyak G, Gnylorybov A, Gyrina O, Hospodarskyy I, Polyvoda S, Smiyan S, Yagensky A, Yatsyshyn R; USA: Ahn C.
Bridging
Infliximab
CTP-13: Developped for RA and AS
17 patients IST in IBD concluded "CT-P13 may have biosimilarity and interchangeability with its originator in IBD.
(https://www.ecco-ibd.eu/publications/congress-abstract-s/abstracts-2014/item/p565-an-experience-of-anti-tnf-biosimilar-ct-p13-use-clinical-efficacy-safety-and-interchangeability-in-inflammatory-bowel-disease-a-pilot-study.html)
NCT01844804: Phase I 146 HV in 1 US site, finalized end 2013, no public results
Watson/Actavis has Phase II trial ongoing


Ferring has FE 999049 In Phase III ongoing in Europe
Pegfilgrastim
Filgrastim
Lipefilgrastim
http://www.nanogenpharma.com/
balugrastim
Full transcript