bettering china's biosimilars

8/11/2019 Bettering China's Biosimilars

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BioCentury, THEBERNSTEINREPORTONBIOBUSINESS MARCH18, 2013 PAGEA9OF2

By Michael J. HaasSenior Writer

While many homegrown biologicsmarketed in China could be perceived asbiosimilars, most are unlikely to meetinternational standards and are not mar-keted as such in China. But with an uptickin returnees and VC investment, and im-provement in manufacturing infrastruc-ture, Chinese companies such asHenliusBiotech Co. Ltd. and InnoventBiologics Inc.are aiming to develop truebiosimilars that could compete in theglobal market.

Current regulations in the EU and U.S.require a biosimilar to have the same amino acid sequence as the

innovator biologic, and glycosylation patterns and other struc-tural features that are highly similar, so that the two productsclosely match in terms of efficacy and safety.

The first step in developing a biosimilar involves rigorousanalyses of the innovator product to identify its amino acidstructure, define the range of its structural variations, anddetermine which variations could affect efficacy and safety.

Those results provide goalposts that guide the design andmanufacture of a biologic that closely matches the original.

Products marketed in China that might be perceived asbiosimilars were not developed with such rigorous upfrontanalyses and might not even use the same recombinant DNAsequence as the innovator biologic in their manufacture, accord-ing to Innovent co-founder, President and CEO Michael Yu.

As a result, these new versions of biologics have loweractivities than the original products and their overall quality doesnot comply with international standards for biosimilars, he toldBioCentury.

He also said most biologic manufacturing facilities in Chinado not comply with international GMP standards and thusproduce versions of biologics that are not as pure as the originalproducts.

Companies in China that market copies of innovator biologicsknow how regulators in the U.S. and EU define biosimilars andknow that their products do not meet that definition, said ScottLiu, co-founder and CEO of Henlius.

Liu added that these products cannot be marketed as biosimilarsin China because SFDA has not yet created a biosimilarspathway. Instead, the products follow the same regulatorypathway as novel biologics, he said.

However, because the copycats have the same generic namesas the innovator products and are approved to treat many ofthe same indications, they can be mistakenly perceived asbiosimilars, said Greg Scott, founder and president of consultancyChinaBio LLC.

It might be better to think of the Chinese versions ofinnovator products as follow-on biologics or modified versionsof the original product rather than biosimilars, he said.

At least two companies in China market versions of etanerceptto treat autoimmune indications.Shanghai CP Guojian Phar-maceutical Co. Ltd.(CPG) markets Yisaipu to treat rheuma-

Product Discovery & Development

Bettering Chinas biosimilarstoid arthritis (RA), polyarticular juvenidiopathic arthritis (JIA), ankylos

spondylitis and plaque psoriasis. Shanhai Celgen Biopharmaceutical CLtd.markets Qiangke to treat the saindications plus psoriatic arthritis.

Amgen Inc.,Pfizer Inc.andTakePharmaceutical Co. Ltd.market Enbetanercept, a recombinant p75 tumor crosis factor (TNF) receptor linked to Fc portion of human IgG1 (TNFr:Fc),treat RA, psoriasis, psoriatic arthritis aankylosing spondylitis.

CPG also markets Xenopax, a versof Zenapax daclizumab, to prevent rej

tion in kidney transplant patients in China. Rochemarke

Zenapax for the indication until 2009, when it withdrew humanized mAb against IL-2 receptor alpha chain (CD25) frthe U.S. and EU due to diminishing demand.

Daclizumab high-yield process (DAC HYP) from AbboLaboratories, AbbVie Inc.andBiogen Idec Inc.is in PhIII testing to treat multiple sclerosis (MS).

Additionally,3SBio Inc.markets EPIAO injectable recomnant human erythropoietin (EPO) to treat anemia and TPIAinjectable recombinant human thrombopoietin (TPO) to tridiopathic thrombocytopenic purpura (ITP) and thrombotopenia.

CPG, Celgen and 3SBio have not reported sales figures any of their products.The companies do not call their produbiosimilar on the English versions of their websites or in thEnglish press releases.

Upward trends

Minimal expertise and a dearth of manufacturing facilicompliant with international GMP have held back biosimilarChina. But the sharp increase in the number of returneincreasing investment in biotech, and the growing markeChina could push through these roadblocks.

A lot of Western-educated Chinese people have returnedChina, but the talent pool for biologics development is still pand scattered among too many companies, said Changlin Ddirector of biotechnology atLuye Pharma Group Ltd.

The returnees dont know how to develop and manufactbiologics and biosimilars according to international standarhe said.

Luye primarily develops small molecules and traditioChinese medicine (TCM) but expanded into biologics in 20when it acquired biologics CRO and manufacturer A-Bio PharPte. Ltd. Dou declined to disclose Luyes biologics pipeline.

Luye is headquartered in Singapore but has four R&D andproduction centers in China and markets multiple produthere.

Another part of the problem is that many investors in Chdont really understand what it takes how much time, hmuch money to bring a biologic or biosimilar to market, s

It might be better to think

of the Chinese versions

of innovator products

as follow-on biologics or

modified versions of the

original product rather

than biosimilars.

Greg Scott, ChinaBio LLC

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between other noncoding RNAs and disease offers some

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of WNT signalingYES1 and RIPK4, respectivelythat

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inhibitors of these kinases.

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scaling up manufacture of the hydrogel, called VentriGel,

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cancer samples; and more

Dou. They just see the size of the market and the potenrewards.

Liu agreed. Most returnees, he noted, have experience oin research laboratories, not industrial experience in developand manufacturing biologics.

He added: Like many of the returning scientists, investdont understand the complexity of biologic and biosimdevelopment. They dont know what theyre getting into.

ChinaBios Scott was more sanguine about the prospectsthe biosimilars.

There is sometruth that expertiseamong returnees islow and spread toothin, but this hasbeen changing overthe last severalyears as companieshave been deliber-

ately recruiting re-turnees with theneeded expertise,he said.

According to the Chinese government, since 1978 thhave been 1 million returnees across all industry secto700,000 of whom have returned to China in just the last years, Scott said.

ChinaBio estimates about one-fifth of all returnees haexperience in life sciences. So the lack of talent in biologics only be a short-term constraining factor, according to Sco

He noted that over the last four years, companies have bebuilding biologics manufacturing facilities that are compliwith international GMP.

Both Henlius and Innovent have or are building such facilitOur manufacturing facility was designed by an EU-ba

firm and will meet purity standards in the U.S., EU and Japasaid Liu of Henlius. We have already recruited key people wthe necessary expertise to operate the facility.

Yu said Innovent has invested $200 million in buildinGerman-designed facility that will meet international GMP stdards. The design was favorably reviewed byEMAandFDAhe said.

The manufacturing lines capable of producing material preclinical development and initial clinical trials are alreaonline, and the lines capable of producing larger quantities be operational by early 2014, Yu said.

We have already hired a few individuals who have extensexperience at big biotech companies in the U.S., he added

Scott also noted that VC investment in China continuesrise. In 2012, total investment across life sciences was $9million, up from $572 million in 2011 and just under the all-thigh of $1 billion in 2010, he said (see Entering New DomainA18).

Investments in drug companies accounted for about 60%the deals and 60% of the amount invested in 2012, Scott sa

While ChinaBio does not break out figures for biologics other sectors within the drug industry in China, another drivfactor is that the interest in novel biologics is also growingChina, said Scott. As companies build talent for develop

The talent pool for

biologics development

is still poor and scattered

among too many

companies.

Changlin Dou, Luye Pharma


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Product Discovery & Development,

from previous page

and manufacturing novel biologics, so, too, will they build talentfor biosimilars.

David Jiang, managing director at BIOCOMs China Con-sulting initiative, said at least two other factors are drivinggrowth of the biosimilars sector in China: government invest-

ments in the healthcare system and the biotech industry, and thegrowing number ofmiddle-class con-sumers with in-creasing purchasingpower and an in-creasing incidenceof chronic diseases.

BIOCOM is atrade associationrepresenting life sci-ences companies insouthern California.

There is no

doubt in my mind that China will become a major R&D base andmajor market for biosimilars, Jiang said. Its just a question ofwhen.

Thinking global

Going forward, Scott and Jiang agreed the major hurdle forbiosimilars development in China is SFDA.

In general, the small size and inexperience of SFDA reviewstaff has resulted in lengthy review times for clinical trials, evenlonger timelines for biologics than for small molecules, and otherregulatory obstacles (see BioCentury, Feb. 25).

More specifically, the agency has not created a pathway forbiosimilars.

SFDA is short-staffed and has no real expertise in biologics,Scott said. Until the agency issues guidance for biosimilars andcompanies see what they have to do, it is hard to say how thesector will grow.

Last November, SFDA announced it would release guidancefor biosimilars but has given no timetable for doing so.

They are moving in the right direction by developing anapproval process for biosimilars, said Jiang.

However, companies like Henlius and Innovent arent waitingfor SFDAs guidance. Instead, they have chosen to developbiosimilars according to international standards.

At Henlius we follow EMA and FDA guidelines for biosimilarsand strive to meet those standards because we intend to market

our products globally, Liu said. We decided very early in thehistory of the company to make quality our first priority and doeverything we can to meet international standards.

Thus, he said, our biosimilar products have exactly the sameamino acid sequence as the innovator products and we doextensive studies of glycan profiles and other structural features,biological function and purity to make sure our products arehighly similar to the originals.

Henlius has two lead products: HLX01, a biosimilar ofrituximab to treat non-Hodgkins lymphoma (NHL) and RA; and

HLX02, a biosimilar of trastuzumab to treat breast cancer. Tcompany submitted INDs to SFDA for the products in Decem2011 and December 2012, respectively.

Liu said SFDA takes about 18 months to review an IND. The expects a re-sponse to the HLX01IND by mid-2013and the HLX02 IND

next year.Weve already

started discussionswith companies inKorea, Turkey, Po-land and Russia aspartners to marketour products out-side China at thesame time as we market them in China, he added.

Innovents lead product, IBI301, is also a biosimilar of rituximdeveloped in accordance with international standards, Yu said. Lyear the company submitted an IND to SFDA for IBI301 to trNHL, chronic lymphocytic leukemia (CLL) and RA.

Innovent expects SFDA to complete its review of the IND2014.

Yu said Innovent plans to market IBI301 in China first, tfind an international partner to help market globally.

Innovent is in discussions with an undisclosed potenpartner, he said.

In addition to IBI301, Innovent has other undisclosbiosimilars and novel biologics in preclinical development.

Biogen Idec and Roches Genentech Inc. unit marRituxan rituximab, a chimeric mAb against CD20 antigen,treat NHL, CLL and RA.

Genentech and Roches Chugai Pharmaceutical CLtd. unit market Herceptin trastuzumab, a humanized magainst EGFR2 (HER2; ErbB2; neu), to treat breast and gascancers.

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, Chin

Shanghai CP Guojian Pharmaceutical Co. Ltd., Shanghai, Chi

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.

Like many of the returning

scientists, investors dont

understand the complexity

of biologic and biosimilar

development.

Scott Liu, Henlius Biotech

There is no doubt in my

mind that China will becoma major R&D base and

major market for biosimilars

Its just a question of when.

David Jiang, BIOCOM

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bettering china's biosimilars

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