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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