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nature biotechnology volume 28 number 9 SEPTEMBER 2010	 883
nothaveaccesstothematpricestheycanafford
or that insurance com...
884	 volume 28 number 9 SEPTEMBER 2010 nature biotechnology
Themainattributesneededforabiosimilarto
succeed in the global ...
Indian Biosimilars Opportunity : Kapil Khandelwal, EquNev Capital, www.equnev.com
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Indian Biosimilars Opportunity : Kapil Khandelwal, EquNev Capital, www.equnev.com

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Kapil Khandelwal
EquNev Capital
www.equnev.com

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Indian Biosimilars Opportunity : Kapil Khandelwal, EquNev Capital, www.equnev.com

  1. 1. nature biotechnology volume 28 number 9 SEPTEMBER 2010 883 nothaveaccesstothematpricestheycanafford or that insurance companies will cover.” At the outset, the Cipla-China partnership is targetingtenmonoclonalantibody(mAb)drugs and fusion proteins against rheumatoid arthri- tis, cancers and allergic asthma for marketing in India and China, particularly drugs that are presently not protected by patent or whose pat- ent term is due to expire. “We are very happy to be partnering with Cipla,” says Xu Shengping, CEO of Shangai- based BioMabs, which is setting up a new biosimilar facility in Shanghai under the col- laboration with Cipla. Their technology will alsobeusedbyMabPharm’sfacilityinGoa.“We expect to launch the first product at the end of 2011,” Hamied says. TheIndianbiosimilarspaceisalreadystrewn with a handful of local firms developing and marketing a broad range of products (Table 1). The space has been bolstered by gov- ernmentincentives and the prospect of less stringent approval require- ments than in the US and Europe. “We have a special scheme for bio- similar makers; it even goes as far as fully supporting clinical trials,” says Department of Biotechnology secretary Maharaj Kishan Bhan. Forinstance,phase1and2trialsforbiogenerics havebeenwaivedbythedrugscontrollergeneral ofIndiaundertheMinistryofHealthandFamily Welfare (US Food and Drug Administration’s Indiancounterpart),andphase3trialswith100 patients are enough for establishing bioequiva- lence.Thishelpsbringdowndevelopmentcosts to $10–$20 million, enabling Indian companies to offer their biosimilars 25–40% cheaper than brandedbiologics,saysSyamalaAriyanchiraan independent pharma-biotech industry analyst in Bangalore. Indian firms may be rushing into the bio- similar space now, but their interest is on the second wave of blockbuster products that will go off-patent between 2012 and 2016 in Europe andtheUS.Suchproducts,whichincludemAbs and fusion proteins, present several challenges compared with simpler biologics, warns Jay Indian generic giant Cipla has begun its foray into biosimilars with an eye firmly on biotech’s blockbusters. The Mumbai-based chemical generics manufacturer is taking aim at top- selling biologics—Roche’s Avastin (bevaci- zumab) and Herceptin (trastuzumab) and Pfizer/Amgen’s Enbrel (etanercept)—which last year brought in a combined $17 billion. With no expertise in biologics, Cipla has had to shoparoundtobuilditsbiologiccapabilities.To this end, on June 15, the company made a $65 million investment in Shanghai-based BioMab and Indian firm MabPharm located in Goa. Although low-cost versions of biotech’s most successfulbrand biologicsrepresentsasubstan- tial opportunity, Cipla will be not only playing catch-up but also competing for market share with multinational pharmaceutical companies that have already ramped up their capacity and expertise in produc- ing biologics (Nat. Biotechnol. 27, 299– 301, 2009). On the other hand, if major generics players from emerging economies meet the technical standardsrequiredfor entryintotheWestern biosimilars market, this may force big pharma to price their follow-on products more competitively. “This is a major decision,” says Yusuf Hamied, Cipla’s chairman, referring to the June announce- ment. The deal will be setting a precedent in that a player with very little presence in biotech extends its strategy to biologics by gearing up for antibody production. “A time will come when the world will be selling only biotech drugs. When that day arrives Cipla will be prepared,” says Hamied. The news was also welcomed by William Haddad, founder and long-time chair of the Generic Pharmaceutical Association in Arlington, Virginia, and currently chairman andCEOofNewYork–basedBiogenerics.“The Cipla-China BioMab agreement should send shiversupthebacksofthebrandbiotechcompa- niesasitunderminesalltheanti-genericbiotech arguments,” he said. “For me the great irony is thatthethirdworldwillhaveaccesstolifesaving biotech medicines that are affordable, whereas patients in the so-called developed nations will India’s Cipla sets sights on Avastin, Herceptin and Enbrel Cipla built its $1.17 billion generics business by offering cheap copies of anti-AIDS drugs. The Mumbai-based firm now aims to copy ten monoclonal drugs against rheumatoid arthritis, cancers and allergic asthma. STR/AFP/GettyImages. TTO patent swap Two medical research funders have agreed to exchange selected intellectual property (IP) assets in a bid to boost commercialization. Cancer Research Technology (CRT) of London and the UK’s Medical Research Council Technology (MRCT) will offer each other the rights to discoveries funded by their respective parent organizations, the charity Cancer Research UK and the government-backed Medical Research Council (MRC). As part of the exchange, CRT will work on an MRC-derived project in cancer, whereas MRCT will reciprocate outside oncology with revenue sharing to be agreed on a case-by-case basis. MRCT and CRT are both ‘super-TTOs’, technology transfer offices, in that both run drug development facilities. CRT’s Development Laboratory and MRCT’s Centre for Therapeutics Discovery each produce preclinical data packages on small molecules and biologicals to add value to the original patented IP. Although the agreement between the two commercialization arms is broad in principle, the first swaps are likely to concern projects that would feed these internal development pipelines. According to Keith Blundy, CEO of Cancer Research Technology, “There are projects that both groups are already working on, but we are not necessarily ‘kitted out’ in the relevant clinical area. We may not have the biological models needed to progress the project.” John Hodgson Brazil bans Bayer A judge has prohibited Bayer Cropscience from marketing Liberty Link corn, a genetically modified crop resistant to Ignite and Liberty herbicides, in Brazil. If the Leverkusen, Germany–based company fails to suspend marketing, planting, transportation and import immediately, it will be fined R$50,000 ($28,500) a day. This ruling issued in July by an environmental court in the southern state of Parana is only the second time a Brazilian court has overturned a commercial GM crop already approved by the country’s technical commission on biosafety (CTNBio), says the commission’s coordinator Jairon Nascimento. The first marketing suspension was in 1998 when a judge blocked Roundup Ready soybeans from Monsanto of St. Louis. It took a further six years to ascertain the commission’s competence to make biosafety decisions related to GM crops, after which a flurry of commercial GM crop approvals followed. The court took action after a civil suit brought by several agriculture and consumer advocacy groups, who argued that CTNBio’s May 2007 approval of Liberty Link maize relied on an inadequate review and neglected post-release safety monitoring. The judge in the Liberty Link case, Pepita Durski Tramontini Mazini, found that CTNBio failed to ensure adequate post-release monitoring of the crop or the potential effects on regional biomes. “The [post-release monitoring] plan is under analysis in CTNBio, but [the court] has not considered this fact,” Nascimento says. Lucas Laursen in brief news ©2010NatureAmerica,Inc.Allrightsreserved.
  2. 2. 884 volume 28 number 9 SEPTEMBER 2010 nature biotechnology Themainattributesneededforabiosimilarto succeed in the global marketplace will be safety, efficacy and, to a lesser extent, pricing. “Simply conducting a small clinical trial would not form thebasisforapprovalofabiosimilarorabiologi- cal in Europe or the USA,” says Robin Thorpe, head of Biotherapeutics at the UK’s National Institute for Biological Standards and Control (NIBSC). Developing nations may not set the bar as high, says Thorpe. He points out that European requirements for biosimilars, which include detailed clinical studies comparing a biosimilar with an approved reference product, are often not adopted in developing nations. Subpar quality of biosimilar products origi- natinginemergingeconomiesisalreadycausing concern.Inonestudyofastreptokinasebiosimi- lar(Nat.Biotechnol.23,413,2005),NIBSCscien- tists found that one batch from India contained no detectable streptokinase protein or activity; what’s more, two batches from the same manu- facturer had only 10% and 20%, respectively, of the labeled potency. Schellekens voices similar worries. “We have tested many products from Asia and South America in our lab in Utrecht but most do not meet our quality standards. All the products that have failed to be approved in Europe came from Asia.” For Haddad, the notion that only a few Western companies have the expertise to suc- cessfully make copies of biologics that will meet thestandardsoftheUS,EuropeanandJapanese regulatory agencies is prejudiced. “Such argu- ments are political and not scientific,” says Haddad. “You must move from chemistry to biology,butthelearningcurvehasbeencrossed and scientists in the generic biotech industry match the competence of the multinationals.” Geena Malhotra, Cipla’s research manager, says the technology to characterize the innovator biotech products is so well established today “that working with the right partner, Cipla is confident that it can develop the biosimilars.” The first biosimilars approved have predom- inantly been simpler recombinant proteins, such as recombinant human growth hormone (Table 1).ButCiplaispursuingmAbs,complex, large molecules, copies of which will probably needextensiveandextendedclinicalevaluation, before approval in any of the major markets. According to Cipla’s Malhotra, the company decided to pursue mAbs for immunology and oncology indications because it represents a good fit with their therapeutic and market- ing experience, and their partner can provide the technological know-how. Cipla’s partner BioMab cites mAbs as ‘ideal drugs’, given their strong specificity, proven efficacy and limited side effects, as reasons for pursuing generic versions—a fact also recognized by the Chinese government, which has specially established the National Engineering Research Center for Antibody Medicine to promote mAb therapies Eric Langer, managing partner in biotech and life sciences marketing firm BioPlan of Rockville, Maryland, believes Cipla has iden- tified an opportunity to cut costs of expensive innovator products, which enjoy high-volume sales.“Thetargetsarelikelytobeforbig-market products,producedatlargerscales—likemono- clonals,” says Langer. Cipla may be making a strategic decision here, says Ariyanchira as “the number of competitors is very few in this area.” Schellekens cautions, however, that the regu- latory demands will be substantial as there are more quality issues with mAbs than there are for recombinant proteins. “And with quality being the Achilles’ heel of the Indian/Chinese biosimilars,itwilltakealotoftimeandconvinc- ing before we will see doctors here [in Europe] using these [mAbs].” At least one Indian company has decided to stay clear of biosimilars. “Biogenerics are not going to become a commercial success and I do not know why every company in India is rush- ing to start the copycat business all over again,” saysKrishnaElla,CEOoftheHyderabad-based Bharat Biotech. “The big pharma in the West would like us to keep perpetually busy copying their drugs while they innovate and bring out newer and better ones,” he says. “The trouble is our companies look at short term for four years or so, and not long term.” Killugudi Jayaraman Bangalore Desai,CEOofUniversalConsultinginMumbai. Biosimilars are never exact replicas of the origi- nals and the ability of Indian companies to gen- erate biosimilars that satisfy the US Food and Drug Administration and European Medical Agency will be the “acid test” for the Indian players, he says. Huub Schellekens of the departments of PharmaceuticalSciencesandInnovationStudies atUtrechtUniversityinTheNetherlandsissimi- larly blunt. “[US and European] markets will be dominatedby big pharma,” he believes. “It takes between50and100millioneuros[$64and$129 million, respectively] to develop a biosimilar that meets the regulations in Europe, the US and Japan… that’s in addition to post-market- ing costs and pharmacovigilance demands,” he adds. “I do not see how a small company, espe- cially from India or China, even if they have the technical skills and money to develop a high- quality biosimilar could be able to compete with Teva, Sandoz or Hospira.” In this context, Gayatri Saberwal, a scientist at the Institute of Bioinformatics and Applied Biotechnology in Bangalore, says, “the easiest way for Indian firms to get a toehold in Western markets is to become a contract manufacturer of biosimilars for large Western companies.” Penetrating the Western biosimilars market may be tough, but it is definitely a battle worth fighting, says Kapil Khandelwal, CEO of EquNev Capital, a health-care advisory services firm in Bangalore. “If you don’t do it, somebody else will,” he says. Table 1 Indian companies marketing biosimilars in India Company (location) Biosimilar Product description Dr Reddy’s Lab (Hyderabad) Grafeel Filgrastim (recombinant granulocyte-macrophage colony- stimulating factor, G-CSF) Reditux Biosimilar rituximab (mAb targeting CD20) Cresp Darbepoetin alfa (recombinant erythropoietin) Intas (Ahmedabad) Neukine Filgrastim (recombinant G-CSF) Neupeg PEGylated G-CSF Intalfa Recombinant human interferon alpha-2b Epofit Recombinant erythropoietin Shantha Biotech/ Merieux Alliance (Hyderabad) Shanferon Recombinant interferon alpha-2b Shankinase Recombinant streptokinase Shanpoietin Recombinant erythropoietin Reliance Life Sciences (Mumbai) ReliPoietin Recombinant erythropoietin ReliGrast Recombinant G-CSF ReliFeron Recombinant interferon alpha-2b MIRel Recombinant reteplase (tissue plasminogen activator) Wockhardt (Mumbai) Wepox Recombinant erythropoietin Wosulin Recombinant insulin Biocon (Bangalore) Eripro Recombinant human erythropoietin Biomab Bioximilar nimotuzumab (humanized mAb targeting epidermal growth factor receptor) Nufil Filgrastim, recombinant G-CSF Myokinase Recombinant streptokinase biosimilar Insugen Recombinant human insulin N E W S ©2010NatureAmerica,Inc.Allrightsreserved.

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