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BioCentury,
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MARCH 18, 2013
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Product Discovery & Development
Bettering China’s biosimilars
By Michael J. Haas
toid arthritis (RA), polyarticular juvenile
Senior Writer
idiopathic arthritis (JIA), ankylosing
“It might be better to think
While many homegrown biologics
spondylitis and plaque psoriasis. Shangof the Chinese versions
marketed in China could be perceived as
hai Celgen Biopharmaceutical Co.
biosimilars, most are unlikely to meet
Ltd. markets Qiangke to treat the same
of innovator products
international standards and are not marindications plus psoriatic arthritis.
as follow-on biologics or
keted as such in China. But with an uptick
Amgen Inc., Pfizer Inc. and Takeda
in returnees and VC investment, and imPharmaceutical
Co. Ltd. market Enbrel
modified versions of the
provement in manufacturing infrastrucetanercept, a recombinant p75 tumor neoriginal product rather
ture, Chinese companies such as Henlius
crosis factor (TNF) receptor linked to the
Biotech Co. Ltd. and Innovent
Fc portion of human IgG1 (TNFr:Fc), to
than biosimilars.”
Biologics Inc. are aiming to develop true
treat RA, psoriasis, psoriatic arthritis and
biosimilars that could compete in the
ankylosing spondylitis.
Greg Scott, ChinaBio LLC
global market.
CPG also markets Xenopax, a version
Current regulations in the EU and U.S.
of Zenapax daclizumab, to prevent rejecrequire a biosimilar to have the same amino acid sequence as the tion in kidney transplant patients in China. Roche marketed
innovator biologic, and glycosylation patterns and other struc- Zenapax for the indication until 2009, when it withdrew the
tural features that are highly similar, so that the two products humanized mAb against IL-2 receptor alpha chain (CD25) from
closely match in terms of efficacy and safety.
the U.S. and EU due to diminishing demand.
The first step in developing a biosimilar involves rigorous
Daclizumab high-yield process (DAC HYP) from Abbott
analyses of the innovator product to identify its amino acid Laboratories, AbbVie Inc. and Biogen Idec Inc. is in Phase
structure, define the range of its structural variations, and III testing to treat multiple sclerosis (MS).
determine which variations could affect efficacy and safety.
Additionally, 3SBio Inc. markets EPIAO injectable recombiThose results provide goalposts that guide the design and nant human erythropoietin (EPO) to treat anemia and TPIAO
manufacture of a biologic that closely matches the original.
injectable recombinant human thrombopoietin (TPO) to treat
Products marketed in China that might be perceived as idiopathic thrombocytopenic purpura (ITP) and thrombocybiosimilars were not developed with such rigorous upfront topenia.
analyses and might not even use the same recombinant DNA
CPG, Celgen and 3SBio have not reported sales figures for
sequence as the innovator biologic in their manufacture, accord- any of their products. The companies do not call their products
ing to Innovent co-founder, President and CEO Michael Yu.
“biosimilar” on the English versions of their websites or in their
As a result, these new versions of biologics “have lower English press releases.
activities than the original products and their overall quality does
not comply with international standards” for biosimilars, he told
Upward trends
BioCentury.
He also said most biologic manufacturing facilities in China
Minimal expertise and a dearth of manufacturing facilities
do not comply with international GMP standards and thus compliant with international GMP have held back biosimilars in
produce versions of biologics that are not as pure as the original China. But the sharp increase in the number of returnees,
products.
increasing investment in biotech, and the growing market in
Companies in China that market copies of innovator biologics China could push through these roadblocks.
know how regulators in the U.S. and EU define biosimilars and
“A lot of Western-educated Chinese people have returned to
know that their products do not meet that definition, said Scott China, but the talent pool for biologics development is still poor
Liu, co-founder and CEO of Henlius.
and scattered among too many companies,” said Changlin Dou,
Liu added that these products cannot be marketed as biosimilars director of biotechnology at Luye Pharma Group Ltd.
in China because SFDA has not yet created a biosimilars
“The returnees don’t know how to develop and manufacture
pathway. Instead, the products follow the same regulatory biologics and biosimilars” according to international standards,
pathway as novel biologics, he said.
he said.
However, because the copycats have the same generic names
Luye primarily develops small molecules and traditional
as the innovator products and are approved to treat many of Chinese medicine (TCM) but expanded into biologics in 2010
the same indications, they can be mistakenly perceived as when it acquired biologics CRO and manufacturer A-Bio Pharma
biosimilars, said Greg Scott, founder and president of consultancy Pte. Ltd. Dou declined to disclose Luye’s biologics pipeline.
ChinaBio LLC.
Luye is headquartered in Singapore but has four R&D and/or
“It might be better to think of the Chinese versions of production centers in China and markets multiple products
innovator products as follow-on biologics or modified versions there.
of the original product rather than biosimilars,” he said.
“Another part of the problem is that many investors in China
At least two companies in China market versions of etanercept don’t really understand what it takes — how much time, how
to treat autoimmune indications. Shanghai CP Guojian Phar- much money — to bring a biologic or biosimilar to market,” said
maceutical Co. Ltd. (CPG) markets Yisaipu to treat rheumaSee next page
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Dou. “They just see the size of the market and the potential
rewards.”
Liu agreed. Most returnees, he noted, have experience only
in research laboratories, not industrial experience in developing
and manufacturing biologics.
He added: “Like many of the returning scientists, investors
don’t understand the complexity of biologic and biosimilar
development. They don’t know what they’re getting into.”
ChinaBio’s Scott was more sanguine about the prospects for
the biosimilars.
“There is some
truth that expertise
“The talent pool for
among returnees is
low and spread too
biologics development
thin, but this has
is still poor and scattered
been changing over
the last several
among too many
years” as companies
companies.”
have been deliberately recruiting reChanglin Dou, Luye Pharma
turnees with the
needed expertise,
he said.
“According to the Chinese government, since 1978 there
have been 1 million returnees across all industry sectors,
700,000 of whom have returned to China in just the last five
years,” Scott said.
ChinaBio estimates about one-fifth of all returnees have
experience in life sciences. “So the lack of talent in biologics will
only be a short-term constraining factor,” according to Scott.
He noted that over the last four years, companies have been
building biologics manufacturing facilities that are compliant
with international GMP.
Both Henlius and Innovent have or are building such facilities.
“Our manufacturing facility was designed by an EU-based
firm and will meet purity standards in the U.S., EU and Japan,”
said Liu of Henlius. “We have already recruited key people with
the necessary expertise to operate the facility.”
Yu said Innovent has invested $200 million in building a
German-designed facility that will meet international GMP standards. “The design was favorably reviewed by EMA and FDA,”
he said.
The manufacturing lines capable of producing material for
preclinical development and initial clinical trials are already
online, and the lines capable of producing larger quantities will
be operational by early 2014, Yu said.
“We have already hired a few individuals who have extensive
experience at big biotech companies in the U.S.,” he added.
Scott also noted that VC investment in China continues to
rise. “In 2012, total investment across life sciences was $982
million, up from $572 million in 2011 and just under the all-time
high of $1 billion in 2010,” he said (see “Entering New Domains,”
A18).
Investments in drug companies accounted for about 60% of
the deals and 60% of the amount invested in 2012, Scott said.
While ChinaBio does not break out figures for biologics and
other sectors within the drug industry in China, “another driving
factor is that the interest in novel biologics is also growing in
China,” said Scott. “As companies build talent for developing
See next page
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BERNSTEIN R EPORT
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Product Discovery & Development,
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and manufacturing novel biologics, so, too, will they build talent
for biosimilars.”
David Jiang, managing director at BIOCOM’s China Consulting initiative, said at least two other factors are driving
growth of the biosimilars sector in China: government investments in the healthcare system and the biotech industry, and the
growing number of
middle-class consumers with in“Like many of the returning
creasing purchasing
scientists, investors don’t
power and an increasing incidence
understand the complexity
of chronic diseases.
of biologic and biosimilar
BIOCOM is a
trade
association
development.”
representing life sciences companies in
Scott Liu, Henlius Biotech
southern California.
“There is no
doubt in my mind that China will become a major R&D base and
major market for biosimilars,” Jiang said. “It’s just a question of
when.”
Thinking global
Going forward, Scott and Jiang agreed the major hurdle for
biosimilars development in China is SFDA.
In general, the small size and inexperience of SFDA review
staff has resulted in lengthy review times for clinical trials, even
longer timelines for biologics than for small molecules, and other
regulatory obstacles (see BioCentury, Feb. 25).
More specifically, the agency has not created a pathway for
biosimilars.
“SFDA is short-staffed and has no real expertise in biologics,”
Scott said. “Until the agency issues guidance for biosimilars and
companies see what they have to do, it is hard to say how the
sector will grow.”
Last November, SFDA announced it would release guidance
for biosimilars but has given no timetable for doing so.
“They are moving in the right direction by developing an
approval process for biosimilars,” said Jiang.
However, companies like Henlius and Innovent aren’t waiting
for SFDA’s guidance. Instead, they have chosen to develop
biosimilars according to international standards.
“At Henlius we follow EMA and FDA guidelines for biosimilars
and strive to meet those standards because we intend to market
our products globally,” Liu said. “We decided very early in the
history of the company to make quality our first priority and do
everything we can to meet international standards.”
Thus, he said, “our biosimilar products have exactly the same
amino acid sequence as the innovator products and we do
extensive studies of glycan profiles and other structural features,
biological function and purity to make sure our products are
highly similar to the originals.”
Henlius has two lead products: HLX01, a biosimilar of
rituximab to treat non-Hodgkin’s lymphoma (NHL) and RA; and
MARCH 18, 2013
P AGE A11 OF 24
HLX02, a biosimilar of trastuzumab to treat breast cancer. The
company submitted INDs to SFDA for the products in December
2011 and December 2012, respectively.
Liu said SFDA takes about 18 months to review an IND. Thus
he expects a response to the HLX01
IND by mid-2013
“There is no doubt in my
and the HLX02 IND
mind that China will become
next year.
“We’ve already
a major R&D base and
started discussions
major market for biosimilars.
with companies in
Korea, Turkey, PoIt’s just a question of when.”
land and Russia as
partners to market
David Jiang, BIOCOM
our products outside China at the
same time as we market them in China,” he added.
Innovent’s lead product, IBI301, is also a biosimilar of rituximab
developed in accordance with international standards, Yu said. Last
year the company submitted an IND to SFDA for IBI301 to treat
NHL, chronic lymphocytic leukemia (CLL) and RA.
Innovent expects SFDA to complete its review of the IND in
2014.
Yu said Innovent plans to market IBI301 in China first, then
find an international partner to help market globally.
Innovent is in discussions with an undisclosed potential
partner, he said.
In addition to IBI301, Innovent has other undisclosed
biosimilars and novel biologics in preclinical development.
Biogen Idec and Roche’s Genentech Inc. unit market
Rituxan rituximab, a chimeric mAb against CD20 antigen, to
treat NHL, CLL and RA.
Genentech and Roche’s Chugai Pharmaceutical Co.
Ltd. unit market Herceptin trastuzumab, a humanized mAb
against EGFR2 (HER2; ErbB2; neu), to treat breast and gastric
cancers.
COMPANIES AND INSTITUTIONS MENTIONED
Abbott Laboratories (NYSE:ABT), Abbott Park, Ill.
AbbVie Inc. (NYSE:ABBV), Chicago, Ill.
Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.
BIOCOM, San Diego, Calif.
Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.
ChinaBio LLC, Shanghai, China
Chugai Pharmaceutical Co. Ltd. (Tokyo:4519), Tokyo, Japan
European Medicines Agency (EMA), London, U.K.
Genentech Inc., South San Francisco, Calif.
Henlius Biotech Co. Ltd., Shanghai, China
Innovent Biologics Inc., Suzhou, China
Luye Pharma Group Ltd., Singapore
Pfizer Inc. (NYSE:PFE), New York, N.Y.
Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland
Shanghai Celgen Biopharmaceutical Co. Ltd., Shanghai, China
Shanghai CP Guojian Pharmaceutical Co. Ltd., Shanghai, China
State Food and Drug Administration (SFDA), Beijing, China
Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, Japan
3SBio Inc. (NASDAQ:SSRX), Shenyang, China
U.S. Food and Drug Administration (FDA), Silver Spring, Md.
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