23 March 2018

COMPANY NEWS 3 Lupin strikes deal for 3 EU report points finger manufacturing mAbs No sell-off planned by 3 Olainfarm’s Maligina at China and India on IP Recipharmsitereadyfollowing investment 4 Hikma’s impairments give 5 hina and India are the main offenders identified in aEuropean Union (EU) report US$747mn loss Con the protection and enforcement of intellectual property (IP) rights that has just Siegfried feels need to keep on acquiring 5 been publishedbythe European Commission’s Directorate-General for Trade. The report –which “helps the Commission to update its list of ‘priority countries’ and to MARKET NEWS 6 focusits efforts and resources on the specificareas of concern, with the aim of protecting Biosimilars market is poised for asurge 6 European companies and consumers from counterfeiting and piracy worldwide” – French bodies battle over 7 highlights “a particularproblem with counterfeit pharmaceuticals”, claiming that 90% substitution “India and China are the biggest producers of counterfeit pharmaceuticals”. “Persistent and longstanding problems”inChina means that the country “continues to be EU slams PhRMA for 7 the toppriority for the EU”,according to the report. As well as counterfeiting, issues identified ‘Special 301’ bullying by the report include difficulties in obtaining interim injunctions;damages awarded for IP FDA breaks down its 8 infringements not compensating for losses or deterring future infringements; concerns over GDUFA performance the quality of granted patents; data-protection practices that discriminate against foreign products; and difficultiesinsecuring protection for trade secrets. PRODUCT NEWS 9 “India also remains abig concern for the Commission,” the report notes, “in particular LG Chem etanercept is 9 due to the lack of suitable protection for pharmaceutical products, and also because India is approved in Korea one of the biggest producers of counterfeit pharmaceuticals.” Meanwhile, “restrictive patentability criteria” and difficulties in enforcement, along with “very broad criteria being applied for Avastin use patent is invalidated by PTAB 9 granting compulsory licences” make effective patent protection in India “very difficult”, Mundipharma lands rights 11 according to thereport. There is also “a worryinglylarge patent backlog” and no effective for trastuzumab system for protecting undisclosed test data generated to obtain marketing authorisations. Noramco and AMPAC ally 11 The report also “highlights that Indonesia, India, and Argentina apply unduly on controlled APIs restrictive criteria for granting patents”. And “in Brazil, the procedures for the granting of Pfenex may go alone to 12 patents in the pharmaceutical sector are not in compliance with international standards”, the launch teriparatide reportstates,citing“the interference of health authorities in the grantingofpatents”. Moreover, “regulatory data protection for pharmaceuticals... is lacking or is not considered adequate in FEATURES 14 countries such as China, Indonesia, India, Mexico and Argentina”. Meanwhile, the European Parliament has complained that US brand body PhRMA is Hikma’s balance sheet is a14 adopting “bullying tactics” to influence the EU’s approach to IP incentives (see page 7). G bonus for chief Olafsson As the US pricing situation continues to bite, industry veteranand newly-appointed Hikma chief executive office Siggi Olafsson is Local courts may decide on data confident the company’s superior balance sheet and diversified business operation, ational courtsofEuropean Union (EU) member states involved in decentralisedmarketing- spread across three regions, will provide a Nauthorisation procedures as aconcerned member state have “jurisdiction to review the competitive advantage. Dean Rudge reports. determination of the point in time from which the data-exclusivity period for the reference medicinal product starts to run”,according to aruling by the European Court of Justice (ECJ). REGULARS However, the competent authority “cannot itself determine the point in time from which the data-exclusivity period for the reference medicinal product starts to run when adopting... its Events – Our regular listing 8 decisiononthe placing on the market of that generic medicinal productinthat member state”. Price Watch UK – Our regular listing 9 “By contrast,” the ECJ ruled, “that [national] court does not have jurisdiction to review Pipeline Watch – Ezetimibe 10 whether the initial marketing authorisation for the reference medicinal product granted in People – Strides’ Kumar takes 16 another member state was granted in accordance with [Directive 2001/83 as amended by back role of chairman Directive 2012/26/EU].” The case –referred to the ECJ by Finland’s Supreme Administrative Court–involved Helm andAstellas,aswell as Finnish medicinesagency Fimea,and revolved Issue No.346 around Helm’s Alkybend (bendamustine), for which adecentralised marketing-authorisation procedure concluded in Finland in March 2014. G

COMPANY NEWS

STRATEGIC ALLIANCES BUSINESS STRATEGY/ANNUAL RESULTS Lupin strikes deal for No sell-off planned by manufacturing mAbs Olainfarm’s Maligina

ndia’s Lupin has signed an agreement with Pune’s CSIR-National lainfarm hasnocurrent plans to sell off any of its subsidiaries, IChemical Laboratory (CSIR-NCL) and Delhi’s Department of Science OaccordingtoIrina Maligina, one of the daughters of the Latvian and Technology (DST)todevelop anovelcontinuous manufacturing firm’s recently-deceased chairman Valerijs Maligins. Responding to process for an undisclosed biosimilar monoclonal antibody (mAb). media speculation, Maligina –who, along with her two sisters, was CSIR-NCL’s process development team –lead by Rahul named in Maligins’ will to inherit his shareholding in the company– Bhambure –willworkincollaboration with Lupin’steam for “developing emphasisedthat “I do not plan to sell sharesofOlainfarm, and neither the target process”. Noting that biotech was one of the firm’s “key do Isupport the sale of any of its daughter companies”. drivers”, Lupin’s senior vice-president and head of research and Stating that “further increase in value” of the Olainfarm group development (R&D) and biotechnology, Rustom Mody,saidthe firm was “my top priority”, Maligina insisted: “I am ambitious about was “committed to advancing our biotech R&D capabilities through medium-termdevelopmentofthe company. Iwill seriously consider strategic partnerships”. The deal was “expected to yield rich dividends any reasonable growth opportunities, including investments in new for the country”, the company added. products and new companies.” “With an increasing demand for biosimilar therapeutics and an Shortly after the death of Maligins late last year (Generics ever-increasing pressure for manufacturing cost reduction,”Lupin bulletin,15December 2017, page 16), the Latvian firm announced stated, “the biopharmaceutical industry is showing keeninterestinthe that Olainfarm’s shares would be “inherited by all children of development of continuousmanufacturing processes.” Maligins in equal parts, with the condition they are not allowed to Existing purification platforms for biosimilar mAbs involved an sell, present or otherwise alienate them during the five-year period integration of two-to-three offline controlled chromatography after the inheritance is received”. processes, the firm pointed out, which “severely limitsthe throughput In February, Maligina and her sister Nika Saveljeva declared and the yield of the target therapeutic product”. that “we see our professional future being related to Olainfarm and Lupin’s YL Biologics joint venture with Japan’s Yoshindo recently other inherited companies”, pointing out they were already minority reported positive results from aglobal Phase III trial for its proposed shareholders ofthe company. That same month, Maliginawas appointed etanercept biosimilar. The firm hopes to file its rival to Amgen’s as the guardian of Maligins’ inheritance by Jurmala’s Orphan Court. Enbrel in Europebythe end of June, and enter the market within the “My approach as aguardian of inheritance will be apragmatic next 18 months (Generics bulletin,16February 2018, page 15). G one, and Iwill do my best possible in the best interests of heirs of Valerijs Maligins,” Maligina stated. “I do care for preservation and the increase of value of Olainfarm and other companies developed by my father. Therefore my actions are targeted in this direction.” BUSINESSSTRATEGY/ANNUAL RESULTS Despite some “unfavourable events, like fluctuations of the ScinoPharm eyes formulations Russian rouble”, 2017 had been “a good year for the company”, Maligina insisted. Olainfarm’s turnover last year lifted by atenth to cinoPharm Taiwan says it is looking to “integrate niche active C122 million (US$150 million), boostedbyupturns in Russia, , Spharmaceutical ingredients(APIs)and to ventureinto formulations”. and , the firm’s “major sales markets”. “Only sales The firm plans to “prioritise the distributionofvertically-integrated in , and Ukraine experienced some reduction,” injectables, including small-molecule injections and peptide APIs”. the firm observed. Last year, ScinoPharm revealed it was establishing its own Product-registration processes were completedinLatvia, , injectable formulations facility(Generics bulletin,24February2017, , and during 2017, Olainfarm noted, page 5). “The injectables plant is being positioned to prepare its andalsofor several medicines produced by NPK Biotest in Belarus. registration batch this year, file an abbreviated new application Registration processes in Nepal, Armenia, , Myanmar, (ANDA) submission in Taiwan, and expects aTaiwan Food and Cameroon and “are still ongoing”, the company noted, while Drug Administration inspection subsequently,” the firm noted. it was “taking all steps necessary to obtain the market authorisations Group sales suffered a13% slide to NT$3.52 billion (US$121 in Turkey, where the first approvals are expected by mid-2018”. million) in 2017. Making up over two-fifths of turnover was North Olainfarm also revealed it was continuing to search for pharma- America, as Europe contributed 29%, India 11%, Japan 9% and related acquisitions, “possibly with different sales markets”. G China 3%. Generic APIs accounted for 69% of group turnover, contract manufacturing 18% and contract research 8%. Royaltiesfor two co-operative projects with Baxter for five injectables and with an undisclosed Indian firm for fondaparinux BUSINESS STRATEGY “increased significantly in the last year”, ScinoPharm stated. Julphar sets goals for growth Meanwhile, paclitaxel shipmentsin2017 declinedbecause of “an inventory reduction by clients”, the firm observed. “Shipments of ulphar says it is “targeting double-digit growth in 2018 with the other major generic were delayed due to the replacement and Jplanned launches of 25 new products in the United Arab Emirates integration of product lines and factories by clients after mergers, and (UAE)” after the UAE-based firm reported sales of AED1.3 billion this has also affected revenue.” However, the “increase in shipment (US$354 million) in 2017. The firm –which has just completed the of APIs and intermediates for four contract research organisation acquisition of Gulf Inject –recently obtained good manufacturing (CRO) projects that are in Phase III clinical trials has offset part of practice (GMP) approval from the Saudi Food and Drug Authority the decline in demand for APIs for generic drugs”. G (SFDA) for its Julphar Saudi Arabia jointventure with CigalahGroup.G

23 March 2018 GENERICS bulletin 3 COMPANY NEWS

MANUFACTURING IN BRIEF DR REDDY’S says its active pharmaceutical ingredient (API) Recipharm site ready ‘Plant 1’ in Telangana, India, has received four ‘Form 483’ observations from the US Food and Drug Administration (FDA) following an inspection. Separately, the Indian firm revealed that following investment its localAPI ‘Plant3’, also in Telangana, received five Form 483s after an audit, that were “related to procedures and facility maintenance”. Reddy’s said the observations at both plants would ecipharm’s blow-fill-seal machinery at its Kaysersberg facility be “addressed comprehensively within the stipulated time”. Rin Alsace, , is “now operational following asubstantial investment” in the plant last year. The C18 million (US$22.2million) ADCOCK INGRAM has announced that its acquisition of OTC and investment adds anew blow-fill-seal high-speed filling and packaging ophthalmics player Genop Holdings (Generics bulletin,22 linetothe site, taking the total number of lines to eight and increasing September2017, page2)is“now unconditional” after all precedent the facility’s manufacturing capacity by 200 million unidoses annually. conditions were met. The SouthAfricanfirm said that Genop would Adding 2,400 sq m, the investment “creates space for afurther “operateasaseparate company” within its Prescriptionsegment. three machines, which will ultimately allow the site to manufacture over 1.2 billion unidoses per year”. “This latest investment is in direct ARDENA says it has “added activepharmaceuticalingredient (API) response to customer demand for single-dose and sterile manufacturing expertise”after acquiring ChemConnection,acontract-manufacturer services, such as aseptic processing for eye-care and ear-care products,” specialising in novel APIs and nanomedicines. This followed a stated Yves Buelens, Kaysersberg general manager, “particularly “series of acquisitions” for Belgium’s Ardena and was part of its from markets such as the US, Turkey, and Canada.” strategy to “form aleading integrated drug-development company The facility specialises in blow-fill-sealtechnology for sterile andreach the C30 million (US$36.9million)sales mark this year”. liquids, and manufactures single-dose units and has an advanced aseptic process for sterile-liquid packaging applications. G QUALI-CONTROLE has received awarning letter fromthe US Food and Drug Administration (FDA) for its drug contract-testing laboratory in Meru, France, concerning its finished-dosage forms. After an inspection in September 2017, the agency found that non- BUSINESSSTRATEGY compendial test methods usedtoanalyse customers’ drug products had not been validated, and out-of-specification results had been NuPharm focuses fully on CNS invalidated “without justification or documented investigation”. uPharm has launched anew website and corporate identity as it N“places its full focus on the treatment of central nervous system PILATUS CLINICAL SERVICES’ Germanfacilities in Brandenburg (CNS) disorders”. “The group’s objective is to have apresence have been awarded aWDL/GDP certificate from the German throughout Europe,” the firm explained, “and to pursue areputation regulatory authorities following arecent inspection. “This will for work that has areal impact on approaches to CNS disorders.” greatly enhance Pilatus’position in Europe and enhance its access As well as “showcasing all of the information concerning its to manufacturers and suppliers in Europe,” the firm stated. drugs”, the website “highlights the dimensions and potentials of this group,its resolutebacking of research and development, its salesforce BIOCON has submitted a corrective and preventive action (CAPA) and its production capabilities”. NuPharm has also unveiled its logo plan to address six ‘Form 483’ observations issued by the US Food of aneurone that “demonstrates its focus on CNS diseases”. and Drug Administration (FDA) to the firm’s Malaysianmanufacturing Createdin2016, NuPharm “isthe result of the strategic combination facility, following apre-approval inspection completed in February. of five pharmaceutical companies”, and investment group Apax Partners. Makingupthe five firmsare Spain’sQualigen, Laboratorios CVS HEALTH’S stockholders have approved the company’s Lesvi and Inke; Germany’s Neuraxpharm; and Italy’s FB Health. acquisition of Aetna,the US’ third-largest health insurer by sales. Developing and marketing branded, generic and nutraceutical The US$69 billion deal “is expected to close in the second half of drugs to treat CNS disorders, NuPharm produces finished-dosage 2018, subject to required regulatory approvals”, CVS noted. G forms and active pharmaceutical ingredients (APIs). G

Issue 346 l 23 March 2018

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Editor: Aidan Fry Deputy Editor: David Wallace Director of Subscriptions: Val Davis Group Sales Manager: RobCoulson Awards Manager: NatalieCornwell Production Controller: DebiRobinson Production Editor: Jenna Meredith Managing Director: Philip Jarvis

Terms &Conditions: See www.generics-bulletin.com/subscribe. [email protected] [email protected] While due care has been taken to ensure the accuracy of information containedinthis publication, the publisher makes no claim that it is free of error and disclaims any liability whatsoever for any decisions or actions taken as aresult of its contents. Assistant Editor: Dean Rudge Business Reporter: Grace Montgomery Published by OTC Publications Ltd, 4Poplar Road, Dorridge,SolihullB93 8DB, UK. Tel: +44 (0) 1564 777550 Fax: +44 (0) 1564 777524 Company registered in England No 02765878. ©OTC Publications Ltd. All rights reserved. Generics bulletin® is registered as atrademark in the European Community. [email protected] [email protected] Printed by Warwick Printing Company Ltd. ISSN 1742-0784

4 GENERICS bulletin 23 March 2018 COMPANY NEWS

ANNUAL RESULTS BUSINESS STRATEGY/ANNUAL RESULTS Hikma’s impairments Siegfried feels need give US$747mn loss to keep on acquiring

mpairments totalling more than US$1 billion linked to the firm’s iegfried intends to keep searching for acquisitions that would IWest-Ward Columbus US non-injectables generics business led Sbolster its Drug Substances active pharmaceutical ingredients Hikma to report aUS$747 million operating loss in 2017. Group (APIs) and intermediates business as well as its Drug Products turnover dipped by 1% as reported to US$1.94 billion on the back finished-dose unit. The Swiss contract development and manufacturing of weaker Injectables sales in the US and afall in Hikma’s Branded organisation (CDMO) has recently made sizeable purchases as its Middle East and North Africa (MENA) business. strove to achieve “critical size and aleading competitive position”. Having taken aUS$35 million impairment in the first half of “As astrategic partner with abroad line-up, organic growth is last year, Hikma was forced to massively reduce its expectations for insufficient to keep up withthe pharmaceutical industry,” maintained the business in the final six months, ultimately resulting in a chief executive officer Rudolf Hanko. “Consequently, Siegfried US$1.08 billion impairment write-off, comprisingUS$920 million in remains open for acquisitions that make industrial sense and can be intangible assets and US$164 million of property plant and equipment. acquired at areasonable price.” Total impairment charges were US$1.11 billion, as the firm swung Hanko argued that the Swiss group’s recent record of retaining from aUS$302 million operating profit year-on-year. customers and order volumes after taking over businesses such as Hikma –which last month appointed Siggi Olafsson as its chief BASF’s API operation or German injectables producer Hameln Pharma executive officer –pointed out that its US$1.94 billion group sales “proved that we are capable of integrating large-scale acquisitions”. Chief financialofficer Reto Suter insisted that “Siegfriedenjoys Business Annual sales Reported Operating sufficient financialscope to carry out larger acquisitions”, including segment (US$ millions) change (%) margin (%) raisingfunds from financialmarkets. “Insufficientcritical size” was, he believed, amore significant business risk than inorganic expansion. US 586 -3 – Outlining Siegfried’s central strategic goals, chief scientific and Middle East, North Africa 103 +13 – strategic officer Wolfgang Wienand said the group would remain Europe/Rest of World 87 +5 – focused on “the continued expansion of critical size and growth Injectables 776 -1 37.8 through entryintonew and attractive segments of the CDMO market, US Generics 615 +2 -176.0 eitherbymeansoforganic growth or acquisitions”.Organic growth initiatives, he said, included Hameln pushing into aseptic filling Branded MENA 536 -4 20.0 of biological products through astrategic partnership with Danish Others 9–-44.4 recombinant antibodiesspecialist Symphogen. Meanwhile, Siegfried expects the API facility that it builtinNantong, China, to be approved Hikma 1,936 -1 -38.6 by the US Food and Drug Administration (FDA) this year.

Figure 1: Breakdown by business segment of Hikma’s sales and reported Wienand said the Swiss group planned to expand its finished- operating margin in 2017 (Source –Hikma) dose capacity and capabilities “by means of an acquisition, either in the US or Europe”. As Siegfried looked to move into adjacent total represented growth of 1% in constant currencies, as the 1% business segments,technologies such as micronisation, spray-drying reported drop came amid “challenging market conditions in the US”. andlyophilisation wouldbeattractive,hesaid,aswouldadding more As Figure 1shows, global Injectablessales also declined by 1% facilities that could handle highly-potent compounds. to US$776 million, driven by a3%fall to US$586 million in the Diversifying into adjoining business segments, improving the US” due to greater competition. “In 2016 and 2017 we launched 26 group’s product offering and expanding its existing operations are new molecules in the US, substantially more than any other generic the three core pillars of the ‘Evolve’ businessstrategy that Siegfried injectables manufacturer,” noted executivechairman Said Darwazah. believes willcarryittoaturnover of at leastSFr900 million(US$943 The majority of these were former Bedford [Laboratories] products, million) and an earnings before interest, tax, depreciation and he said, with Hikma “around halfway through bringing back the amortisation(EBITDA)margin of about 20% “in the medium term”. Bedford portfolio”. Hikma expected to receive regulatoryapproval “We plan to reach this level of growth by optimising internal structures “for afurther 10 to 15 products in 2018”, he revealed (see page 14 and acquiring strategically suitable companies,” Wienand explained. for amore detailed look at Hikma’s strategy). Last year, Siegfried –which has just reacquired adrug-product For MENA Injectables, chief financial officer Khalid Nabilsi facility in Zofingen, , from Arena Pharma –increased observed, sales “accelerated as expected in the second half of the its turnover by 4.6% to SFr751 million (see Figure 1), while its year across all markets, reaching US$103 million, an increase of 13%, EBITDA margin strengthened by 1.7 percentage points to 15.2%. G or 23% in constant currency”. Hikma also benefitted from launching n [email protected] partner Celltrion’s Remsima (infliximab) biosimilar “in new markets”. Generics turnover in the US climbed by 2% to US$615 million, Product Annual sales Change Proportion although Hikma underlined that2016 included only a10-month group (SFr millions) (%) of total (%) contribution from the firm’s acquisition of the former Roxane business. Drug Substances 580.7 +4.1 77 Signifying pricing pressure in the US, and the firm’s continued failure to launch generic Advair (fluticasone/salmeterol), Hikma is Drug Products 169.8 +6.3 23 forecasting non-injectable Generics sales of US$550-US$600 million Siegfried 750.5 +4.6 100 in 2018. Theinitial forecastfor 2017 had been US$800 million. G n [email protected] Figure 1: Breakdown by productgroup of Siegfried’s sales in 2017 (Source–Siegfried)

23 March 2018 GENERICS bulletin 5 MARKET NEWS

MARKET RESEARCH Biosimilars market is poised for asurge

“new wave of biosimilar competition and Aopportunity” will emerge in developed markets this year, according to an Iqvia report analysing healthcare trendsfor the industry up to 2022. Entitled ‘2018 and beyond: outlook and turning points’, the report states that this year “US$19 billion of current biotech spending in developed markets will have competition from biosimilars for the first time”. Iqvia analysed biotech medicine spending and biosimilar competition in 10 ‘developed markets’, including Australia, Canada, France, Germany and Italy, as well as Japan, South Korea, Spain, the Figure 1: Biological medicines annual spending newly exposed to biosimilar competition between 2017 and 2032, based on 2016 sales values (Source –Iqvia) UK and the US. Stating that the US$19 billion figure was “significantly greater than the US$3 that the next decade will provide sufficient incentives to encourage billion in biosimilar revenue that became exposed in 2017”, the biosimilar challengers,”the report continues, “the greatestuncertainty report points out that this amount also “adds to the US$26 billion around biosimilars is whether all of the medicines that can be already facing competition”. challenged in the next decade will indeed face competition.” “The new exposure to competition in 2018 is the largest single- Highlighting 10 biologics that will face new or expanded year change to date, and signals the start of the next large wave of competition in the developed markets, the report cited AbbVie’s biosimilars,” Iqvia maintains. From 2019 to 2022, the market researcher Humira (adalimumab), which could see biosimilar rivals in the US predicts, another US$52 billion is expected to face biosimilar “as early as 2019”. However, Iqvia acknowledges, out-of-court competition for the first time in developed markets (see Figure 1), settlements could see the drug retain market exclusivity until 2023. including US$37 billion from the US. “By 2027, 77% of current Turning to small-molecule drugs, the report states that volume biotech spending will be subject to some form of competition.” growth for both existingbranded and generic medicinesindeveloped markets over the next five years from 2018 to 2022 “will remain Spending may rise slow, with the ongoing shifts towards newer medicines over time”. “The impact on competitive molecule spending ranges from a With “slower growth in China and other pharmerging markets”, the 10% increase to a30% decrease,” Iqvia continues, “meaning the “majority of medicine use and spending in these countries continues US$71 billion exposedtocompetition from2018-2022 could result in to be for generic medicines”. “Pharmerging markets will be driven US$50-US$78 billion in spendingfollowing biosimilar entry.” by volume changes and the use of generics, and will grow by 7-8% The potential forhigher spending could come from“incremental in 2018,” the report estimates, projecting market growth by 2022 of demand due to lower prices, or from ineffective competition”, the 6-9% to US$345-US$US375 billion. report points out, with the amount of spending dependent on the Of “particular importance” in China, Iqvia asserts, are the new number of competitors and the speed with which they enter the market, generics quality and efficacy evaluation guidelines, which are intended and the extent to which they compete on price. to drive the registration and development of bioequivalent generics. “The partofthe market subject to biosimilar competition remains “Currently, off-patent originators account for about 18% of spending arelatively small part of biotech spending,” thereport notes,“because in China, and estimates range from 50-85% of that spending could only seven molecules of the 196 currently marketed have faced shift to bioequivalent, locally-produced generics within the next biosimilar competition, to date.” With the total market for biotech five years,” the report notes. medicines reachingUS$168 billionacross developed markets in 2016, In China and other pharmergingmarkets, Iqvia observes, policies there is a“heightened interestbeingplaced on the role of biosimilars, to negotiate prices for higher cost drugs, and to encourage generic which is set to expand significantly”, Iqvia contends. use and domestic manufacturing, are all part of the range of approaches However, a“number of challenges” remain with biosimilars, countries are using to generate predictability in their exposure to the researcher states, in addition to “intellectual property, litigation, healthcare costs. G clinical development and regulatory hurdles”. “While overall it appears n [email protected] IN BRIEF IN BRIEF EMA –the European Medicines Agency–has sent to the European ANSM –France’s medicines agency –has published aset of Union’s budgetary authority the dossier on its planned move to recommendations on naming medicines,aimed at “preventing permanent new premises in Amsterdam,the , .This, potential risks linked to the choice of name”, following aconsultation. the EMA said, was a“key step in the building approval process”. In particular, the agency noted risks of confusion with another Meanwhile, the agency has also published anew tracking tool medicine or product, as well as errors related to the target patient “showing the main milestones and deliverables” for its relocation. population, indications or method of use.

FDA –the US Food and Drug Administration –has published revised EDQM –the European Directorate for the Quality of Medicines – guidance on regulatory classification of pharmaceutical co-crystals. has released revised guidance for electronic submissions for The document details data requirements for applicants and guides certificate of suitability (CEP) applications. “Applicationforms have on characterisation and release testing. G been updated accordingly,” to reflect format requirements. G

6 GENERICS bulletin 23 March 2018 MARKET NEWS

REGULATORY AFFAIRS INTELLECTUAL PROPERTY French bodies battle EU slams PhRMA for over 90% substitution ‘Special 301’ bullying

wo French pharmacists unions –the FSPF and the USPO – Sbrand industry association PhRMA is adopting “bullying tactics” Thave taken opposing stances on whether to sign up to the latest Uto try and influence the EuropeanUnion’s (EU’s) approach remuneration contract with local health insurer CNAM, which to intellectual property (IP) incentives, according to the European includes agoal of achieving a90% generic substitution rate for Parliament’s working group on innovation, access to medicines eligible prescriptions in 2018. Last year, both unions agreed an 86% and poverty-related diseases. PhRMA’s lobbying of the US Trade goal for 2017 (Generics bulletin,31March 2017, page 6). Representative to place the EU on its watchlist in its upcoming 2018 The FSPF announced that it had decided not to sign the agreement. ‘Special 301’ report on IP (Generics bulletin,23February 2018, Explaining its reasons, the union referred to the “significant rise in page 1) was “the latest in afamiliar pattern of efforts by pharmaceutical the substitution rate”, and insisted that this would “render the corporations to coerce and pressurise governments through their substitution rate difficult to achieve”. Against last year’s backdrop various lobby groups”, the working group insisted, expressing its of an 86% substitutionrate, the FSPF pointed out, anational average “strong condemnation” for PhRMA’s request. of 87.5% had been achieved. In particular, PhRMA had highlighted concerns over proposals Moreover, the FSPF said the terms of the revised substitution for an exemption to allow generics firms to manufacture in Europe agreement would lead to an overall reduction of at least C25 million for stockpiling or export during the term of asupplementary protection (US$31 million) in remuneration for pharmacists and would remove certificate (SPC). Apublic consultation on the subject was launched abonus offered to those achievingthe highest substitution rates. by the European Commission in October and concluded in early Further lossesrelated to other matters would cost pharmacists another January (Generics bulletin,20October 2017, page 1). C100 million, the FSPF claimed, urging fresh negotiations with the “The EU shouldnot be penalised or discouragedfrom reviewing government to secure the future of French pharmacies. thenegative impact ofthe currentIP-relatedincentives on biomedical However, the USPO has signed up to the remuneration agreement, innovation, as requested by the EU Council Conclusions on insistingthat it has “chosenthe side of patients, and not of commerce”. ‘strengthening the balance in the pharmaceutical systems in the EU USPO president Gilles Bonnefondsaidthat in doing so, the union and its member states’,” the working group insisted, referring to a had made a“strategic choice”. G reviewofincentives instigated by the EuropeanCouncil in June 2016 (Generics bulletin,24June 2016, page 5). “We recommend that the European Commission continue its enquiry into how different IP incentives, and SPCs in particular, contribute to high medicines prices and therefore undermine universal access to treatment.” PhRMA’s tactics were the latest attempt by originators to try to prevent governments from “usinglegal means to safeguard access Drug Delivery SolutionsPvt Ltd to medicines, and pursue reforms which would better balance public health, access to medicines and competition with IP regimes”, the working group pointed out, illustrating its statement with examples. “Pharmaceutical companies, backed by the US government, Prednisolone 5,10 mg have exerted continued pressure on India to offer more monopolies, stringent IP enforcement mechanisms and amoratorium on compulsory Soluble Tablet licensing,” the working group said, adding that this was “at the expense Bioequivalent to Prednesol® Tablets 5mg, ConcordiaUK of access to affordable medicines and public-health safeguards”. Meanwhile, “at this very moment, PhRMA and the US government EU dossiersready forDCP are currently pressuring the Colombian government to step back Domperidone 10 mg ODT from efforts to introduce generic competition in response to the Fenofibrate160 mg Tablet, 200,267 mg Capsule unaffordable price of ’ cancer drug Gleevec (imatinib)”. “If both the Indian and Colombian governments cave to this Levocetirizine 5mgODT pressure, it could severely restrict access to affordable medicines in Meloxicam 7.5,15 mg ODT the future, with disastrous consequences,” the working group declared. Metformin 750 mg SR Tablet Noting thatseveral PhRMA members wereEuropean firms,the Ondansetron 4,8 mg ODT working group urged them to “clearly distance themselves fromboth this crude attempt to quash legitimate debate and investigation into Racecadotril 10,30 mg Taste Masked GranulesinSachet the impactofbusiness models on the health of theirfellow European Tramadol +Paracetamol 37.5 +325 mg Tablet &ODT citizens, and PhRMA’s demands to sanction developing world Zolpidem 5,10 mg Sublingual Tablet &ODT countries for using legal means to secure affordable medicines”. Calling on the EU to “stay firm in the face of US corporate Athena has an EU GMP approved facility for pressure and to renew its commitment to review its IP incentives Granules, Tablets, Capsules &Sachetlines. system”, the working group emphasised that it was “of critical importance to respect countries’ sovereign rights to uphold health Operations Get in Touch safeguards availableunder the World Trade Organization (WTO) Europe :[email protected] www.athenadds.com agreement on trade-related aspects of IP rights (TRIPS)”. G Rest of World :[email protected] [email protected] n [email protected]

23 March 2018 GENERICS bulletin 7 MARKET NEWS

EVENTS – April, May, June REGULATORY AFFAIRS 17-19April FDA breaks down its n DIA Europe 2018 Basel,Switzerland Issues including policy and regulations, research and development, GDUFA performance marketing and access will be covered at this three-day event. Contact:Drug Information Association. Tel: +41 61 225 5151. quarterly report detailing the performance of the US Food and E-mail: [email protected]. Website: www.diaglobal.org. ADrug Administration (FDA)’s Generic Drugs Program has been publishedfor the first time by the agency, as part of commitments 25 April outlined in the second iteration of the Generic Drug User Fee n 14th Legal Affairs Conference Amendments (GDUFA II), which was implemented from 1October London, UK last year (Generics bulletin,1September 2017, page 1). This one-day conference organised by Medicines for Europe will The new quarterly performancemetrics focus on the number of cover legal and intellectual-property developments regarding abbreviated new drug applications (ANDAs) awaiting action from generics and biosimilars. This event will be followed by the 16th the applicantorthe FDA,aswell as the mean and median times taken Biosimilar Medicines Conference, at the same venue. for an application to obtain tentative or final approval. Contact:Lucia Romagnoli. Tel: +44 7562 876 873. By the end of the FDA’s first quarter ended 31 December 2017, E-mail: [email protected]. Register online at it recorded that 2,055 ANDAs were awaiting action from the agency, www.medicinesforeurope.com/events. while there were 1,701 ANDAs awaiting applicant action. Meanwhile, 379 tentatively-approved submissions were awaiting action. 26-27April Turning to mean approval time, for final approvals this stood at n 16th Biosimilar Medicines Conference 41.7 months,the FDA noted, whilefor tentative approvalsitwas 32.9 London, UK months.Medianapproval times for final and tentative submissions This Medicines for Europe conference will look at the latest were 41.9 and 29.9 months respectively. As of the end of December, regulatory topics, market access and procurement, and the agency observed there was one ANDA awaiting FDA action that international developments within the biosimilars industry. was subject to priority review. Contact:Lucia Romagnoli. Tel: +44 7562 876 873. 57 ANDA approvals to date in 2018 E-mail: [email protected]. Register online at www.medicinesforeurope.com/events. Separately, data recently released by the agency shows that approving 25 final ANDAs in January and 32 in February gave 23-24May the Office of Generic Drugs (OGD) within the FDA atotal of 57 n World Biosimilar Congress USA 2018 ANDA approvals in calendar 2018 so far. Within these first two months, the OGD received atotal of 146 ANDAs, with 91 of these San Diego, USA obtained in January and 55 awarded in February.The FDA recently The agenda for this two-day meeting includes pricing, reported it had approved or tentatively approved 1,027 generic drugs pharmacovigilance, bioanalytics and patent issues. during 2017, “more than any other year in the history of the generic Contact:Terrapinn. Tel: +1 212 379 6320. drug program” (Generics bulletin,16February 2018, page 10). E-mail: [email protected]. Website: www.terrapinn.com. Tentative approvals granted by the FDA so far in 2018 amount to 11, with six approved in January and the remaining five given 13-15June last month. Atotal of 491 completeresponses were issued, with the n Joint Medicines for Europe and majority –307 –issued in January,followedby184 in February. IGBA Annual Conference The OGD in January refused to receive 11 ANDA applications, Budapest, Hungary withdrew 90 submissions, and made 64 drug master file (DMF) This joint Medicines for Europe and IGBA three-day conference completeness assessments. During thatmonth, the agency received will look at the latest developments within the industry. 54 prior-approval supplements (PASs), with 453 changes being effected (CBE)supplements. Data for February in these areas “requires Contact:Lucia Romagnoli. Tel: +44 7562 876 873. additionalverification and will be posted when available”. G E-mail: [email protected]. Register online at www.medicinesforeurope.com/events.

24-28June REGULATORY AFFAIRS n DIA2018 Pacific alliance will harmonise Boston, USA This is afour-day event which will cover topics including clinical edicines agencies from three countries –Chile, Colombia and trials, the biosimilars landscape, and regulatory issues. MMexico –have signed aco-operation agreement to speed up Contact:Drug Information Association. Tel: +41 61 225 5151. registration through regulatory harmonisation, including on E-mail: [email protected]. Website: www.diaglobal.org. bioequivalence and good manufacturing practice (GMP). The ISP, Invima and Cofepris agencies have also “created apermanent technical team to consolidate the harmonisation and regulatory convergence”. SAVE THE DATE... Stating agoal of strengthening the pharmaceutical market and Tuesday 9October 2018, “expanding access for the population to awider range of medicines Madrid, Spain at abetter price”, the three agencies agreed to share information, strategies and best practice as part of the co-operation scheme. G

8 GENERICS bulletin 23 March 2018 PRODUCT NEWS

AUTOIMMUNE DISEASES TREATMENTS ONCOLOGY DRUGS LG Chem etanercept Avastin use patent is is approved in Korea invalidated by PTAB

outh Korea’s LG Chem has obtained approval in its domestic ll five claims of US patent 7,622,115 –covering methods for Smarket for the firm’sEucept (etanercept) biosimilar of the Enbrel Atreating cancer with Roche’s Avastin (bevacizumab) oncology (etanercept)autoimmunediseases treatmentthat Pfizermarkets in Korea. treatment –have been declared as invalid by the Patent Trial and The approval was based on “large-scale clinical trials”,according Appeal Board(PTAB)ofthe US Patent and TrademarkOffice (USPTO), to LG Chem, including Phase III clinical trials that began in 2014 following inter partes review proceedingsinitiated by Hospira. “for 185 patients in 30 hospitals in Korea, and data on large-scale The ‘115 patent claims methods for treating cancer comprising efficacy and safety validation for Korean patients”. With this data administering bevacizumab and assessingthe patient for gastrointestinal behind it, LG Chem expects to “penetrate the market quickly”. perforation. It discloses that bevacizumab may be administered with LG Chemnoted that it had received approval for an auto-injector chemotherapeutic agents such as fluorouracil and leucovorin, and formulation that would facilitate use for patients with rheumatoid that gastrointestinal perforation can occur in treatedpatients receiving arthritis, employing “a thinner needle than the original”. The SureClick bevacizumab with such chemotherapeutic agents. auto-injector is one of four Enbrel formulations, which also includes Debating construction of the phrase “assessing the patient for apre-filled syringe, multiple-dose vial and the proprietary Enbrel Mini gastrointestinal perforation”, Hospira argued that this should be single-dose prefilled cartridge with AutoTouch Reusableauto-injector. interpreted to mean “evaluating the patient in any way that may In 2015, Korea’s Ministry of Food and Drug Safety approved provide information about whether the patient may be experiencing Merck Sharp &Dohme and Samsung Bioepis’ Brenzys (etanercept) agastrointestinalperforation”. However, Roche’s Genentech claimed biosimilar (Generics bulletin,2October2015, page 25). that the construction should be “taking diagnosticsteps to determine LG Chem saidthe market in Korea for Enbrel was worth around whether agastrointestinal perforation exists”, arguing thatHospira’s KRW30 billion (US$27.9 million). Sales of Enbrel in Pfizer’s proposed construction was so broad that it could cover visual ‘Developed Rest of World Markets’ –comprising Japan, Canada, inspections from aphysician observing apatient with abdominal pain, Australia,South Korea and New Zealand –fell by 7% as reported to and so “effectively removesall meaning from the concept of ‘assessing’ US$395million last year, accordingtothe originator. someone for gastrointestinal perforation in particular”. At the start of this year, Japan’s Mochida Pharmaceutical won But while the PTAB said the patent’s prosecution history “does approval in Japan for the etanercept biosimilar that Mochida and not supportabroadest reasonable construction of this phrase”toindicate LG Chem co-developed. LG Chem says it is “preparing to enter the generally assessing apatient for signs and symptoms of gastrointestinal domestic and Korean markets simultaneously”. G perforation, neither did it accept Genentech’s construction. “We construethe phrase‘assessing the patientfor gastrointestinal perforation’ as indicating atargeted investigation,directed specificallytoconfirming PRICE WATCH ...... UK the presence or absence of gastrointestinal perforation,” the PTABstated. And after considering several pieces of prior art cited by Hospira – including a2000 Genentech press release disclosing adverse events Pioglitazone prices rocket connected to atrial evaluating bevacizumab in combination with verage UK trade prices for pioglitazone tablets increased by leucovorin, as well as Kabbinavar Phase II trial results citing adverse Aseventoeight times for certain presentations in the first half events including gastrointestinal haemmorrhage in association with of March, according to the latest figures reported by WaveData. the use of bevacizumab in combination with fluorouracil and leucovorin – Comparing average UK trade prices between 1-28 February the PTAB found that Hospira had “shown by apreponderance of 2018 and 1-19 March 2018, WaveData calculated that packs of the evidence thatclaims 1-5 of the ‘115 patent are unpatentable”. 28 pioglitazone 15mg tablets had seen an average price rise of “We conclude that aperson of ordinary skill in the art would 718% to £6.05 (US$8.50), despite the lowest offer advancing by have had adequate reason to assess patients with colorectal cancer just 8% to £0.27. For 30mg tablets, the average rise was 630% to receiving bevacizumab in combinationwith chemotherapeutic agents, £6.94 despite packs stillbeingavailable at an unchanged cheapest such as the patients disclosed in Kabbinavar and the 2000 press price of £0.49.And for 45mg tablets, a613%average increaseto release, for gastrointestinal perforation,” the PTAB summarised. £8.04 came as the lowest recorded offer even dropped by 6% to Meanwhile, Amgen has recently filed amotion to dismiss £0.47. All averages were calculated from at least 44 data points. Delaware districtcourt patent litigationwith Genentech over Amgen’s Other significant average pricerises included fluoxetine 60mg Mvasi(bevacizumab-awwb) biosimilar. capsules in 30-count packs rising by 431% to £24.88, as well as According to Amgen, Genentech’s claim that Amgen failed packs of 20 cefradine 500mg capsules jumping by 376% to £13.27. to comply with the ‘patent dance’ outlined in the Biologics Price Meanwhile, pregabalin capsules in several presentations Competition and Innovation Act (BPCIA) framework “does not state sufferedprice drops of between afifth and two-fifths. The steepest aclaim upon which relief can be granted”. Moreover,Amgen states, pregabalin average pricedecline registered by WaveData was 40% Genentech was seeking “de facto injunctiverelief to prohibit Amgen to £7.85 for 84-tablet packs of the 25mg strength, while 300mg from engagingincommercial activity without establishing that such capsules in 56-count packs suffered acomparatively gentle fall injunctive relief is properlybased on any valid and infringed patent”. of just 22% to £6.28. G “Injunctive relief in this case requires plaintiffs establish, among other things, that they can win on the merits of their patent- Up to the minute live retail market pricing is available for the UK and Eire on Wavedata Live at wavedata.net. infringement claims,” Amgen’s partly-redacted filing states. “The Alternatively, contact Charles Joynson at WaveData Limited, UK. court should decline to exercise jurisdiction and dismiss.” G Tel: +44 (0)1702 425125. E-mail: [email protected]. n [email protected]

23 March 2018 GENERICS bulletin 9 PIPELINE WATCH Ezetrol faces entry of EU ezetimibe rivals

ix-month paediatric extensions to supplementary protection Towards the end of last year (Generics bulletin, 15 December Scertificates (SPCs) covering Merck Sharp &Dohme’s (MSD’s) 2017, page 1), the Court of Justice of the EU (CJEU) upheld a Ezetrol/Zetia (ezetimibe) are set to expire in most decision by the UK’s Intellectual Property Office (UKIPO) to deny (EU) member states in mid-April this year (see Figure 1). Those an SPC for the Atozet combination. This was because at the point SPCs refer to European patent EP0,720,599 –which is entitled at which MSD had applied for an SPC in the UK, the company did ‘Hydroxy-substituted azetidinone compounds useful as not hold avalid marketing authorisation, but rather only an end of hypercholesterolemic agents’ –orits national equivalents. procedure notice issued by reference member state (RMS) Germany IQVIA, which maintains the Ark Patent Intelligence Expiry as part of adecentralised regulatory procedure. Database, observes that MSD also owns another European molecule April will also see the expiry of base SPCs protecting AbbVie’s patent, EP1,347,987, running until December 2021. However, the Humira (adalimumab) blockbuster across the EU. However, the ‘987 patent, covering sugar-substituted azetidinones, has lapsed in a originator will enjoy protection via six-month paediatric extensions large number of member states due to anon-payment of fees. running until October this year. Under the terms of aglobal patent- “Hence, with the end of the SPC on EP0,720,599 and no other litigation settlement struck with AbbVie last year (Generics bulletin, valid barrier,”IQVIApoints out, “Ezetrol/Zetia generics may be free 6October 2017, page 1), Amgen plans to launch its Amgevita to enter European markets in April 2018.” (adalimumab) biosimilar in Europe on 16 October this year. Further The cholesterol-lowering agent makes an attractive target for competition to the world’s best-selling drug could come from Samsung generics developers. Merck said Ezetrolsales in the “majorEuropean Bioepis’ Imraldi and Boehringer Ingelheim’s Cyltezo adalimumab markets”inwhich its SPCextensions will expireduringApriltotalled biosimilars, both of which have been approved by the European US$552 million last year, making up alarge chunk of the firm’s Commission, while the European Medicines Agency (EMA) was, as International Ezetrol/Zetia sales outside of the US that edged up by of 5March,evaluating five adalimumab applications. 2% to US$992 million last year. However, global sales of the brand In terms of data exclusivity, Novartis’ Arzerra (ofatumumab) loses almost halved to US$1.34 billion as US sales tumbled by 78% to its EU monopoly during April (see Figure 2). However, the chronic US$352 million following Glenmark and Par’s launch of ageneric lymphocytic leukemia (CLL) treatment may not be an attractive in December 2016 under the terms of apatent-litigation settlement. candidate for biosimilar developers. In January this year, Novartis’ In Europe, MSD has also used the ‘599 patent to protect other partner, Genmab, announced that the Swiss firm intended to “transition ezetimibe-based brands through SPCs. The firm’s Inegy (ezetimibe/ the commercial availability of Arzerra to limited availability via simvastatin) combination is covered by SPCs running until early compassionate-use programs for treatment of CLL in non-US markets”. April next year. However, the originator has faced hurdles in using This decision reflected the low number of Arzerra users outside of the same patent to protect its Atozet (ezetimibe/atorvastatin) brand. the US owing to the availability of several other CLL drugs. G

SPC expiries in April Data exclusivity expiries in April INN Country INN Country Adalimumab Austria, Belgium, Bulgaria, Denmark, Finland, Aflibercept Australia France, Germany, Greece, Hungary, Ireland, Crizotinib* Canada Italy, Luxembourg, Netherlands, Norway, Dienogest/Estrogen South Korea Poland, Portugal, Romania, Slovakia, Slovenia, Dutasteride/Tamsulosin** European Union Spain, , Switzerland, UK Fidaxomicin Australia Agomelatine Portugal Lixisenatide Australia Ofatumumab** European Union Bevacizumab* Czech Republic, Hungary, Slovakia Pasireotide Turkey Enfuvirtide Austria, Belgium, Denmark, France, Ireland, Perflubutane South Korea Italy, Luxembourg, Netherlands, Portugal, Ramucirumab*** US Spain, Sweden, Switzerland, UK Siltuximab*** US Tocilizumab South Korea Ezetimibe* Austria, Belgium, Czech Republic, Denmark, Vildagliptin Switzerland Finland, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Netherlands, *This will be followed by ano-marketing period of two years during Portugal, Spain, Sweden, UK which anotice of compliance will not be granted to ageneric manufacturer. ** This will be followed by two years of market exclusivity, where ageneric or Tigecycline* Finland, Hungary, Norway, Slovakia biosimilar will not be placed on the market *** This will be followed by eight years of biosimilar application approval exclusivity, *expiry of paediatric extension during which abiosimilar will not be approved

Figure 1: Molecules for which supplementary protection certificates (SPCs) Figure 2: Molecules for which data exclusivity expires in certain markets during expire in certain markets in April 2018 (Source –Ark Patent Intelligence) April 2018 (Source –Ark Patent Intelligence)

This monthly update of key patent, SPC and data exclusivity data is extracted from IQVIA’s Ark Patent Intelligence Expiry Database. Covering 130 countries and over 3,000 INNs, Ark Expiry Database contains watertight data teamed with the ultimate in generic launch analysis. For further information, visit www.arkpatentintelligence.com or e-mail: [email protected].

10 GENERICS bulletin 23 March 2018 PRODUCT NEWS

ONCOLOGY DRUGS CONTROLLED SUBSTANCES Mundipharma lands Noramco and AMPAC rights for trastuzumab ally on controlled APIs

undipharma and Celltrion have furthered their partnership in ontrolled-substances specialist Noramco has struck adeal with MEurope for the Korean firm’sportfolio of biosimilars after CAMPAC Fine Chemicals (AFC) through which the active Mundipharma obtained the exclusive distribution and marketing pharmaceutical ingredient (API) manufacturer will supply Noramco rights to Celltrion’sHerzuma (trastuzumab) in seven EuropeanUnion with arange of controlled substances in theUS. Under the terms of (EU) countries,including Germany, Italy and the UK. the strategic partnership, “Noramco will continue to be the marketer The agreement–whichfollows Celltrionreceiving EU approval and will utilise AFC as the contract-manufacturer to supplement forHerzuma last month –comes shortlyafterMerckSharp &Dohme existing Noramco capacity”, the firms stated. launched Samsung Bioepis’ Ontruzant (trastuzumab) biosimilar in AFC –which has current good manufacturing practice (cGMP) the UK (Generics bulletin,16March 2018, page 10). facilities in the US –will produce “certain Drug Enforcement The other four countries covered by Celltrion and Mundipharma’s Administration (DEA) controlled substancesfor use in the treatment agreement are Belgium, the Netherlands, Ireland and Luxembourg, ofaddiction, abuse-prevention, cannabinoids for clinical indications, aspokesperson for Mundipharma revealedtoGenerics bulletin. and for the treatment of attention deficit hyperactivity disorder”. “We don’t have aspecific launch date,” the spokesperson noted “The DEA schedule II and III controlled-substance APIs are in response to Generics bulletin enquiries.“We will aim to launch bulk actives for regulatedpharmaceutical finished-dosecustomers,” after all requisite approvals and reimbursements have been sought.” Noramco and AFC explained, adding that these substances “require Both Herzuma and Ontruzantare versions of the 150mg powder high-quality cGMP production assets and sophisticated analytical for concentrate for solution for infusion formulation of Roche’s equipment to meet very precise quality requirements”. Herceptin (trastuzumab) treatment for breast and gastric cancer. Alarge-scale controlled substancemanufacturing plant recently Mundipharma also holds marketing and distribution rights for registered by AFC in Petersburg, Virginia, would “give Noramco Celltrion’s Remsima (infliximab) and Truxima (rituximab) biosimilars, the extra capacity it needs to meet growing demand”, the firms and began rolling each biosimilarout in European markets in February observed, as well as “a support facility to complement its in-house 2015 and the second quarter of last year respectively (Generics capabilities in Wilmington, Delaware”. bulletin,27February 2015, page 1; 3March 2017, page 1). G James Mish, president and chief executive officer of Noramco, said the firm had “investigated anumber of sites and partners”, but said that only AFC had “both the infrastructure and analytical capabilities in place” to meet Noramco’s needs. Observing that AFC “brings core capabilities like our own”, Mish said the firm was “the first company we have found that integrates well with Noramco’s operations and strategic focus”. Citing AFC’s “long-standing relationship with Noramco in supporting the production of their controlled substances”, AFC president and chief executive officer Aslam Malik said Noramco’s quality, staff and customer-supportculture “closely aligns with AFC’s”. Malik said AFC’s strategic objective would remain “value-created growth achieved by continuing to serve our key customers”, as well as “by expanding our product lines and applying our core technologies to their criticalneeds”. “The foundation of this growth is established through AFC’s core strengths in process research and development and process engineering,” he added. G

RESPIRATORY DRUGS France adds to its répertoire iogaran, Urgo and Upsa havehad carbocisteine 750mg/15ml oral Bgel added to France’s répertoire ofsubstitutable genericequivalents in agroup with ’s Rhinathiolasthe reference brand. At the sametime,Medipha’s diclofenac 75mgprolonged-release tablets and lacidipine 2mg tablets have been listed in new groups against Novartis’ Voltarene and Boehringer Ingelheim’s Caldine brands respectively. Mendelikabs has had nitisinone2mg, 5mg and 10mg capsules included in groups with Swedish Orpham Biovitrum’s Orfadinasthe reference brand. Meanwhile, Medisol’strimebutine 50mg/5mlinjectable solution has been listed against Pfizer’s Debridat, and Sandoz’ vildagliptin/metformin 50mg/850mg and 50mg/1,000mg authorised generics of parent firm Novartis’ Eucreas have also joined the répertoire.G

23 March 2018 GENERICS bulletin 11 PRODUCT NEWS

OSTEOPOROSIS DRUGS IN BRIEF DR REDDY’S has launched a“first-to-market” generic version of Pfenex may go alone UCB’s Xyzal Allergy 24HR (levocetirizine)5mg tablets into the US store-brand OTC sector of the allergy market. to launch teriparatide EMA –the European Medicines Agency –has revealed that from the endofJanuary to theend of February, the number ofbiosimilar pegfilgrastim dossiers being evaluatedbyits committee for human fenex is consideringmarketing itself the PF708 teriparatide medicinal products (CHMP) increased from six to eight. The Ptherapeutic equivalent to Eli Lilly’s US$1.7 billion Forteo committee also received one application for biosimilar bevacizumab osteoporosis brand forwhich the US-based firm intends to file through and one for hydroxycarbamide. the US 505(b)(2) hybrid regulatory pathway in the third quarter of this year. “We are in initial stages of exploration to potentially bring AMNEAL has obtained approval from the US Food and Drug the product to market ourselves,” president and chief executiveofficer Administration (FDA) for, and launched, erythromycin 250mg Eef Schimmelpenninkdisclosed. At the same time, he added, Pfenex and 500mgtablets. Thetherapeutic equivalenttoArbor’s reference- was evaluating “commercial partnership opportunities” for PF708. listed drug “is the only other immediate release oral tablet available”. Having already shown bioequivalence of PF708 to Forteo in healthy subjects –aswell as achieved “high-titer protein production TEVA has been sued by Corcept Therapeutics in aUSdistrict and competitive cost of goods”through its expression platformbased court for filing an abbreviated new drug application (ANDA) for on pseudomonas fluorescens bacteria –the San Diego-based firm ageneric version of the latter’s Korlym (mifepristone)300mg expects during the second quarter of this year to report top-line tablets. Corcept claims in the New Jersey suit that the Israeli immunogenicity data from aPhase III trial for which the firm visited firm’s proposed generic will infringe US patents 8,921,348 and the last of 181 participating patients in mid-February. Secondary 9,829,495, which expire in 2028 and 2036 respectively. endpoints included pharmacokineticsand bone-mineral density. Withafamily of US teriparatide formulation patents set to expire BIOGARAN has introduced in France atenolol/nifedipine on 8December this year –followed by expiry for three method-of- 50mg/20mg capsules equivalent to AstraZeneca’s Ténordate treatment patents on 19 August 2019 –Pfenex believes it may be antihypertensive. Packs of 30 and 90 capsules have pre-tax list able to launch its PF708 candidate in the third quarter of next year prices of C5.60 (US$6.88) and C15.96 respectively. with a“clear, commercially succinct pathway”, whether or not its hybrid application receives an ‘AB’ therapeutic equivalence rating ZYDUS CADILA has received final approval from the US Food from the US Food and Drug Administration (FDA). The firm’s and Drug Administration (FDA) for omeprazole/sodium “US-basedsupply chain” was “fully ready to rampupfor commercial bicarbonate 20mg/1,100mg capsules. The Indian company has launch”, Schimmelpennink revealed. also secured final approval from the agency for tizanidine 2mg While US patent 7,517,334 protects Lilly’s Forteo device until and4mg tablets. March 2025, Pfenexinsistsithas a“strong intellectual-property strategy” and has a“functionally equivalent pen device”. Schimmelpennink ALVOGEN hasobtained an exclusive licence to market in Russia last year told Generics bulletin that the feedback fromuser testing Mithra’s contraceptivevaginal ring made of ethylene vinylacetate of the penapplicator had been “very encouraging” (Generics bulletin, co-polymers.Belgium’s Mithra and its US marketing partner 8September 2017, page 18). Mayne Pharma have just had the contraceptive ring accepted for For its PF582 and PF529 biosimilar candidates to Lucentis filing by the US Food and Drug Administration (FDA) ahead of a (ranibizumab) and Neulasta (pegfilgrastim), Pfenex has paused planned launch in the first half of 2019. clinical developmentto“considerstrategic partnership opportunities”. G LUPIN has obtained final US approvalfor ageneric rivaltoTaro’s Topicort (desoximetasone)0.25% topical spray. Separately, the India firm has launched Tydemy,generic alternatives to Bayer’s ERECTILE DYSFUNCTION DRUGS Safyral (drospirenone/ethinylestradiol/levomefolate calcium) Dutch dosing patent is invalid 3mg/0.03mg/0.451mg tablets and levomefolate 0.451mg tablets, shortly after receiving FDA approval. tadalafil dosage patent thatEli Lilly licenses fromIcos is invalid Adue to lack of inventive step, adistrict court in the Netherlands DNDI –the Drugs for Neglected Diseases Initiative –and fellow has ruled. In reaching its verdict on the Cialis (tadalafil)patent, the non-profit organisation Mundo Sano are teaming up with companies district court in The Hague referred extensively to aUKCourt of to “manufacture and supply anew, more affordable hepatitis C Appeal finding to the same effect last year (Generics bulletin,10 treatment in Latin America”. Egypt’s Pharco will supply the November2017, page 13). active pharmaceutical ingredients (APIs) for sofosbuvir and In invalidating the Dutch part of European dosage patent ravidasvir,while Insud Pharma and Argentinian research and EP1,173,181 –which describes oral doses of tadalafil up to amaximum development company Laboratorio Elea Phoenix will register, of 5mg per day –the Hague court also noted that Germany’s patent manufacture and distribute the drugs in Latin America. court had last year invalidated the ‘181 patent. Askilled person seeking to optimise the dosage of tadalafil would, STRIDES SHASUN hasreceived US approval for its generic the Hague court said, have combined knowledge of dosing for the version of Bristol-Myers Squibb’s Sustiva (efavirenz)600mg first-in-classcompound sildenafil with the Daugan prior-artreference tablets. The Indian company has also revealed it is set to launch that discloses tadalafil as atreatmentfor erectile dysfunction within ranitidine 75mg tablets,its rival to the Zantac heartburn remedy, doses of 0.5mg to 800mg per day. Aseriesof“non-inventive steps” following a150mg strength recently introduced through ajoint would have led the skilled person down a“one-waystreet” to the venture with Vivimed (Generics bulletin,9March 2018,page 12).G claimed dosages, the Dutch court concluded. G

12 GENERICS bulletin 23 March 2018

BUSINESS STRATEGY Hikma’s balance sheet is a bonus for chief Olafsson

As the US pricing ith 2018 marking 40 years since Hikma Pre-filled Pharmaceuticals’inception as asmallcompany syringes and situation continues to Wbased in Jordan mainly supplying branded Small and large autoinjectors parenterals bite, industry veteran generics, the firm felt the time was ripe to unveil a 27 new global brand platform, which includes afresh 89 and newly-appointed logo and visual identity. The “most notable change to the Hikma brand Hikma chief executive since the company’s foundingin1978”, Hikma’s new Infusion officer Siggi Olafsson is brand platform –“Better Health. Within Reach. Every bags Day” –isalso “the beginning of anew chapter in the 47 confident the company’s company’s history”, in the words of the Jordanian superior balance sheet firm, which has transformed “from humblebeginnings” into a“US$2 billion global generic medicines business” and diversified business over the course of its four-decade history. The man tasked to oversee that new chapter is operation, spread across Hikma’s newly-appointed chief executive officer, Complex Lyophilised 13 three regions, will industry veteran and former Teva and Actavis executive 47 Siggi Olafsson.Lastmonth, hetook the role from Said Figure 1: Breakdown by product type and presentation of provide acompetitive Darwazah, Hikma’s chairman and chief executive Hikma’s 223-strong US injectables pipeline (Source –Hikma) officer, who became executive chairmanofthe company advantage. (Generics bulletin,23February 2018, page 1).Darwazah “As we work together and define our long-term Dean Rudge reports. feels Olafsson “is the right person to take the business strategy, we’re in avery nice position. Hopefully we to the next level.” can do some good things as we move on.” Just three weeks into the role –and less than 12 Just over two years ago, Hikma claimed to have months sincehis departurefrom Teva, where he was “transformed” its “position and scale” in the US non- presidentand chief executive officer of the firm’s injectables generics market by taking control of Boehringer erstwhile Global Generic Medicines group –Olafsson Ingelheim’s Roxane business –since renamed West- faced investors as Hikma presented its 2017 financial Ward Columbus (Generics bulletin,7August 2015, results,and revealedhehad spent hisfirst days “flying page 3) –augmenting its West-Ward Pharmaceuticals to different sites” across Hikma’s vast global network business in Eatontown,New Jersey. “I believe that the in order to get aflavour of the company. US Generics business will be an important part of the “I’ve visited all the US sites,” he noted. “I spent strategy of Hikma going forward,” Olafsson stated. last week in Oman. In aweek-and-a-half I’m going to However, given the current pricing environment Portugal.The first impression is great,” he insisted. in the US, impairment charges of more than US$1 “The ingredients in the company are quite amazing, billion linked to the West-Ward Columbus business, there’s still avery strong entrepreneurial spirit.” following are-evaluation, ultimately dragged Hikma Making alarge impression on Olafsson is the to asizeable operating loss in 2017 (see page 5). stateofHikma’s balancesheet,which featured “record” Against this backdrop, Hikma has been keen to operating cash flow of US$443 millionin2017, Hikma drive greater efficiencies and cut costs for its Generics has just reported, up from US$293 million in 2016, business in the last two years, and Olafsson revealed allowing Hikma to reduce its net debt from US$697 his initial priority would be “getting more out of the million to US$546 million year-on-year. “It’s great to pipeline”. “We’reinvesting 6-7% of our revenues into join acompany with this kind of balance sheet. I’ve research and development. But for us to launch, maybe, seen alot worse in my life. It’s abreath of fresh air only six-to-eight products per year, and with the pricing for me to comeinto this situation,”Olafssonsaid. environment we have in the US, if you want to continue “It’s alittle bit premature to say how we’re going growth it’s probably not enough,” he observed. to use this strong balance sheet,” he acknowledged. “I don’t think we need to invest more,” Olafsson However, he insisted it was “amazing”, compared to underlined. “We need to get more efficiency, more “some of our peers, withoutmentioning any names”. “I output, out of the research and development, and maybe thinkwehave the flexibility that some of them don’t have, focus alittle more on differentiating the portfolio, to look for both organic and inorganic opportunities.” because we have the expertise to deliver the most Darwazah added that, “historically we have been technically challenging products out there.” acompany that has done alot of acquisitions, so we Ultimately, Olafsson reflected, Hikma had “the have that kind of experience, and of course Siggi has investment,the people,the technology,the equipment, avery similar background”. So, Darwazah noted, “when the beautiful facilities”. “We really have the ingredients you put all our resources together, with this flexibility to do even more than we’re doing today. And this is we have, with this ability to increase borrowing, it notacriticism of what we have today. Today is really gives us alot of opportunity”. good, but Ijust want more.”

14 GENERICS bulletin 23 March 2018 BUSINESS STRATEGY

“I think what we have is something special,” Region Annual sales Reported Proportion Olafsson concluded. “I like the business due to the (US$ millions) change (%) of total (%) size. In my previous life, Ihad aUS$6 billion headache in the US. Now it’s only US$600 million. So it’s the US 1,201 -1 62 right size, it’s adifferentiated business.” Middle East, North Africa 630 -2 33 In 2017, Hikma pruned its US Generics pipeline of Europe, Rest of World 103 +8 5 37 drugs “to focusonthe most valuableopportunities”, UK 2-33 – as year-on-year the firm’s pipeline fell from 73 in- Hikma 1,936 -1 100 development assets to 40, and 27 filed applications to 20, leading to acut in research and development spending. Figure 2: Breakdown by region of Hikma’s sales in 2017 (Source –Hikma) Current paragraph IV opportunities in the firm’s non-injectables pipeline include Ampyra (dalfampridine), but we’re on the right track.” Vascepa(icosapent ethyl), Fetzima (levomilnacipran), Turning to injectables, Olafssonsaidhewas “very Norvir (ritonavir) and Banzel (rufinamide), as well proud”ofHikma’s globalbusiness, which was “showing as Saphris (asenapine), Xtandi (enzalutamide), Uloric amazing results”, following investments and afocus on (febuxostat), Noxafil (posaconazole) and Xyrem efficiencies. In the US, the firm has amassed astrong (sodium oxybate). While Hikma had implemented “a pipeline coveringmorethan200 presentations addressing significant reduction” of its pipeline, Darwazah noted, amarket of around US$5 billion (see Figure 1). “we also now have capacity to add new products to Morethan two-fifths, or 44%, of these opportunities our pipeline to deliver long-term growth.” had been filed with the FDA, Hikma noted, while the Moreover, as part of Hikma’s cost-cutting measures, restwereatvarious stages of development. In terms of the firm in November announced plans to consolidate the firm’s portfolio, which has more than80products, its oral-dosage manufacturing operations in the US greater than two-thirds have sales of US$5 million or (Generics bulletin,17November 2017, page 4). less, “reducing concentration risk”, while 53% of the “We havealso decided to consolidate our warehouse portfolio boasts two competitors or less. and distribution facilities in the US,” revealed Darwazah, Meanwhile, Olafsson observed that there “might “which will mean we’ll close our distribution centre be some opportunities” to expand Hikma’s injectable in Memphis, [Tennessee], later on this year.” Chief products footprint in Europe, astrategy advocated by financial officer Khalid Nabilsi revealed Hikma had the company under Darwazah’sstewardship. already reduced the headcount of former Roxane “Maybe not in all the markets,” he said, for now staff members by approximately 200. ruling out the Netherlands, for its “low prices”, and Queried on Hikma’soverallefficiencies, and how furtherexpansion in Germany. “Butthe Nordic market they compared to his previousemployers, Olafsson said still has areasonable price,” he noted, underlining this was like “comparingapples with oranges”, but that that Hikma did not have many injectables approved he nevertheless thought about them from “three points”: in the region. “We need to be selective where we go cost of goods sold; product mix; and “the cost of the in, if we want to do this,” he stated. operation”. One strategy advocated by Olafsson was the And in the Middle East and NorthAfrica(MENA) opportunity to furthertransfer productioninto Hikma’s region, Olafsson lauded Hikma for “investing in “high quality, relatively low cost” Jordanian manufacturing manufacturing plants [in locations]where localisation plant and the “high quality, bigger, technically capable” happens and many of the global companies leave the former Roxane site in Columbus, Ohio –“one of the market”. “We’re taking more injectables projects into most beautiful plants that I’ve ever visited”. theMENA,”henoted. Meanwhile, he enthused about “But we need to fill [Columbus] up with more Hikma’s exclusiveagreements withCelltrioncovering products,” he insisted. “So Ithink there’s opportunity three of the Korean firm’s biosimilar products across [for efficiencies] in the cost of goods sold. That will the region –Remsima (infliximab), Herzuma take time of course,but Ifeel we have the ideal scenario (trastuzumab), and mostrecently Truxima (rituximab), “I don’t think we need to [with the two plants].” following an agreement late last year. Asignificant challenge for Hikma and Olafsson Darwazah summarised that Hikma had been invest more. We need continues to be gaining approval for an AB-rated successful in three strategies for its overall injectables to get more efficiency, substitutable generic Advair (fluticasone/salmeterol) business: increasing capacity for “top-line” products, in the US. Earlier this month, Hikma was told by the including lyophilised products; concentrating more output, out US Food and Drug Administration (FDA) to complete “tremendously” on the cost and efficiencies of facilities; an additional clinical endpoint study to support its and investing in the pipeline. of the research application, followingadispute-resolution process with “The facilitieswehave in Portugal areextremely, and development” the US agency(Generics bulletin,16March 2018, page extremely efficient,” Darwazah highlighted, noting 1). This had followed receipt of acomplete response that Hikma was increasing capacity in the existing letter in May last year. facility, andwas also building adedicated oncology “I’m excited for generic Advair,” Olafsson facility. “The cost of unit in Portugal is about athird underlined in response to numerous investor queries. of what it is in Cherry Hill [in New Jersey].” “There are challenges that we’vespoken to the market Having inherited an almost US$2 billion global about, for sure, but they’re challenging for everybody. business, where athird of sales stem from the MENA This is not an easy product. The FDA hasn’t been region, and more than three-fifths from the US (see comfortable in approving anyone,” he said, indicating Figure2), Olafsson revealedthat he had been “excited” to complete response letters also handed out to Mylan about Hikma’s “diversified businesses into threeregions” and Sandoz. Ultimately, “we’re on the right track”, before joining the company, where, “when you have Olafsson insisted. “It could take alittle bit of time, headwinds in one, you can grow the other two”. G

23 March 2018 GENERICS bulletin 15 PEOPLE

APPOINTMENTS IN BRIEF MEDICINES FOR EUROPE –the European off-patent industry Strides’ Kumar takes association –has elected Polpharma’s presidentand chief executive officer, MarkusSieger,toits executivecommittee.“With Markus’ membership of the executive committee,” Polpharma stated, “the back role of chairman interests of local Polish manufacturers will be high on Medicines for Europe’s working agenda.” The firm highlighted the mooted European supplementary protection certificate (SPC) manufacturing trides Shasun’s Arun Kumar is set to return to an executive waiver as “of the most important policy developments which is Srole with the company,less than 12 months after giving it up of major importance to the Polish industry”, adding that it was as part of abroader shake-up of Strides’ board that was designed to “actively working” on the subject with local Polish industry “guide the management team in rolling out future strategies”. association PZPPF. Kumar –founder of the legacy Strides Arcolab business –will take up the role of executive chairman of the board from 1April at LAURUS LABS has appointed quality head Venkata Lakshmana the request of Strides’ board, having in May last year moved over to Rao Chunduru as executive director for afive-year period non-executive chairman (Generics bulletin,26May 2017, page 16). beginning 8March 2018. He replaces Srihari Raju Kalidindi, “Considering the recent transformational challenges faced by who has resigned from the post “due to personal reasons”. thepharmaindustry, the board felt that Arun Kumar’sexperience in theindustry would be of immense value,” Strides disclosedina JOHNSON MATTHEY hasappointed Jason Apter as chief filing, acknowledging the “strategic initiatives and executive of the firm’s health sector. Apter –who has previously directions taken by the current leadership”. served as vice-president of research at Merck’s MilliporeSigma Strides’ turnover rose by 3% to Rs7.54 billion (US$116 million) and as vice-president and managing director of the Asia-Pacific in its financialthird quarter ended 31 December 2017, entirely due region for Sigma-Aldrich –will be based in the US. to sales in the firm’sRegulatedMarkets business segment –including the US and Australia –rising by 29% to Rs5.85 billion, as sales in CMA –the UK’s Competition and Markets Authority –has named ‘Emerging/Institutional Markets’ plunged by two-fifths to Rs1.69 Andrea Gomes da Silva as executive director for markets and billion(Generics bulletin,16February 2018,page 6). Shashank Sinha, mergers, replacing Andrea Coscelli who has been promoted to Strides’ managing director,commented at the time the firm’s “top chief executive. At the same time, George Lusty hasbeen appointed line in the US and Australia is growing ahead of industry and peers”. senior director for consumer protection, succeeding Nisha Arora Strideshas confirmedthat Sinha and executivedirector of who has joined the Financial Conduct Authority. finance Badree Komandur willmaintain their current roles. G ENDO director Jill Smith has decided not to stand for re-election at the company’s annual general meeting on 7June 2018. This was due to her appointment as president and chief executive DEVELOP WINNING officer of “venture creation” firm Allied Minds in May 2017. DISTRIBUTION STRATEGIES MEDICINES AUSTRALIA is seekinganew chief executive officer after the brand industry organisation’s current chief, Milton Catelin, resigned from the role.

AGC BIOLOGICS has named two vice-presidents of business development. Axel Schleyer will take on the role for the North America region, while Christoph Winterhalter handles business OTC DISTRIBUTION IN EUROPE development for Europe. Both will report to the contract development and manufacturing organisation’s chief business officer Robert Broeze. 2018 EDITION DISRUPTION CHANGES PFIZER has appointed Dan Littman to its board of directors. THEPLAYING FIELD At the same time, immunologist Littman has joined Pfizer’s corporate governance and science and technology committees. Now in its 11th edition, this in-depth study identifies the SANOFI’S board of directors has proposed the appointment of factors driving change in the supply network serving Europe’s Schneider Electric’s Emmanuel Babeau as independent director non-prescription and OTC for the French firm at ageneral shareholders’ meeting on 2May. self- sectors. Robert Castaigne will not seek anew term. It provides acomprehensive, data-driven analysis of the SANDOZ’ former vice-president for public affairs in the US, unfolding strategies required to WendySussman,has joined EMD Serono –the biopharmaceutical achieve competitive success. business of Merck–asvice-president of US healthcare, government OVER 20 COUNTRIES AND300 and public affairs. She succeeds Michael Ruggiero. GRAPHS, TABLES &FIGURES ALVOGEN has named Bojung Park to join the firm’s leadership team in Korea as regulatory affairs director. “Her knowledge and Available soon to download or order ® expertise gainedfrom over16years working in the pharmaceutical JAMES DUDLEY online at www.james-dudley.co.uk MANAGEMENT® industry will be avaluable asset,” the company insisted. G

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