gen 7-9-18 pgs.1-24 · 2018. 10. 29. · “tevaannounced multiple plant closures anda15% reduction...

7 September 2018

US deal is slammed onten-year bio exclusivityAproposed 10-year data exclusivity period for biologics set out as part of a trade

agreement-in-principle reached between the US and Mexico must be rejected by thetwo countries, as well as Canada, according to a joint statement by off-patent industryorganisations representing the three territories.

“This provision would harm the growing biosimilar industry, which aims to provide pricecompetition to some of the most expensive prescription drugs and allow patients to benefitfrom affordable medicines,” insisted Mexican body Amegi, along with the US Association forAccessible Medicines (AAM) and the Canadian Generic Pharmaceutical Association (CGPA).“The US, Mexico and Canada should reject these provisions, which would benefit brand namedrug companies to the detriment of public health and the affordability of medical care.”

US President Donald Trump claimed that the deal reached with Mexico – resulting fromrenegotiating the North American Free Trade Agreement (NAFTA) – “modernises andrebalances the trade relationship to reflect the realities of the 21st century”, including “strongand effective intellectual property (IP) protections”. Indicating that the NAFTA label would notbe used for the new trade deal – and that the existing NAFTA deal would be terminated –Trump also indicated that “Canada will start negotiations shortly”. “I think we’ll give thema chance to probably have a separate deal,” Trump suggested, “or we can put it into this deal”.

CGPA president Jim Keon said the generics and biosimilars industries were “gravelyconcerned” by the agreement-in-principle between the US and Mexico, pointing out that as wellas the 10 years of data protection for biologics the deal also included “potentially other IPmeasures that go beyond Canadian law”. “Canada,” Keon added, “must reject any pharmaceuticalIP proposals that go beyond its current laws, which were amended in September 2017 as aresult of concessions made by Canada to reach a comprehensive economic and trade agreement(CETA) with the European Union.”

“Increased pharmaceutical IP measures would have the effect of delaying access to moreaffordable prescription medicines for provincial governments and private drug plans, whileincreasing the cost of prescription drugs as a result of longer IP protection periods,” Keonwarned. “Concessions cannot be made in the area of pharmaceutical IP.” G

Judges considering record entriesArecord number of entries for the Global Generics & Biosimilars Awards 2018 are now

being considered by a panel of expert judges, in preparation for the event that will takeplace on the evening of 9 October 2018 at the Palacio Municipal de Congresos in Madrid,Spain. More than 60 entries were received across 13 Awards categories, all of which will beconsidered by our judges as they decide how best to reward this year’s greatest achievementsacross the generics and biosimilars industries.

The latest sponsor to join the Awards is Masters Specialty Pharma, which has offered itsbacking for the Award for Company of the Year in the Americas region.

This year, the Awards – which are free to attend – for the first time offer companiesthe opportunity to book a dedicated table for the evening, with corporate livery andcomplementary drinks for you and your colleagues.

A full shortlist of nominations highlighting the frontrunners for each of the Awards willbe published in the 21 September issue of Generics bulletin. Gn For more details of how to book a table or reserve tickets to attend the Awards, please contact Natalie Cornwellat Generics bulletin. Call +44 1564 777550 or email [email protected].

COMPANY NEWS 3

Mayne sees a chance 3as US rivals regroupItaly’s Olon expands through 3Indian plantSiegfried is preparing for 4an FDA site visitEmcure’s Marcan has Ottowa 5head officeAdcock calls for rise in 5South African SEPKyowa Hakko Bio is hit 7with FDA warningLannett makes plans for JSP 8deal finishingScinopharm chases opportunities 8in USFour Indian firms get plant 9nods from FDAPfizer urges action on 9biologics denigration

MARKET NEWS 12

SA scheme opposes a rise 12in country’s SEPEU task force works to 12alleviate shortagesBGMA seeks clarity on 13reference productsFrance adds three to similar 13biologics list

PRODUCT NEWS 15

FDA examines cause of 15valsartan impuritySandoz’ Binocrit will replace 16Eprex in NZCelltrion aims to file 16Remsima SC productBiogaran is first with 17French trastuzumabGlenmark inks a deal for 17Spiriva in Europe

REGULARS

Events – Conferences and meetings 8Price Watch UK – Our regular listing 17Pipeline Watch – Vortioxetine 18People – Mexico’s Genomma 20hands Brake top job

Issue No.367

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3GENERICS bulletin7 September 2018

COMPANY NEWSBUSINESS STRATEGY/ANNUAL RESULTS

Mayne sees a chanceas US rivals regroupRestructuring and reorganisation among some of the US generics

industry’s largest competitors – including Teva, Sandoz andMylan – represents an opportunity for Australia’s Mayne Pharma, thecompany believes, after bouncing back from “a challenging first half”in the second half of its financial year ended 30 June 2018.

“The US pharmaceutical market continues to be extremelydynamic,” Mayne observed. “A number of major participants such asTeva, Mylan, Perrigo and Novartis/Sandoz have announced plans tocomplete strategic reviews, restructure...or divest certain US assets.”

“Teva announced multiple plant closures and a 15% reduction inworkforce; Endo restructured its generics operations and refocusedon brands and sterile injectables; and Perrigo announced the separationof its prescription business, including a possible sale or merger,” Mayneoutlined, also claiming that “Novartis is selling its US Sandoz genericsunit”. “The company views this dynamic environment favourably.”

“Key strategic initiatives” included “diversifying channels tomarket, growing [our] share of marketed products” and “extractingproduct cost savings from optimising the supply chain network”. Maynesaid it had made progress “with several generic products transferredin-house during the year which have contributed to improved productmargins in the second half”. Earlier this year, Mayne opened a newUS$80 million facility in Greenville that more than quadrupled itsUS oral-solid capacity (Generics bulletin, 27 April 2018, page 5).

The company “expects to achieve further cost savings from futureproduct transfers through accessing lower manufacturing costs at newcontract manufacturers or active pharmaceutical ingredient (API)suppliers, or gains from overhead recovery throughput benefits”.

While annual sales fell by 7% to A$530 million (US$383 million)and the firm reported earnings before interest, tax, depreciation andamortisation (EBITDA) that almost halved to A$117 million –following asset impairment charges of A$184 million in the first half,largely relating to a portfolio of products acquired from Teva (Genericsbulletin, 2 March 2018, page 6) – chief executive officer ScottRichards drew a distinction between the first and second halves.“Following a challenging first half,” Richards said, “the company’sperformance was substantially stronger in the second half, withrevenue up 18%”, partly driven by “a stabilising generics market”.

Sales through the Generic Products Division (GPD) saw growthdriven by dofetilide, liothyronine, doxycycline, budesonide andcarbidopa/levodopa, although this was more than offset (see Figure 1)by “pricing pressures largely focused in the oral contraceptive portfolio”.Mayne insisted that generics had “performed strongly in the secondhalf, driven by six new product launches, normalised levels of stockobsolescence, improving business mix and cost savings from the transferof manufacturing of select products into Greenville and Salisbury”.n [email protected]

Business segment Annual sales(A$ millions)

Change(%)

Grossmargin (%)

Generic Products 385.7 -8 46

Metrics Contract Services 63.1 +9 53

Mayne Pharma International 36.8 +7 22

Specialty Brands 44.7 -28 84

Mayne Pharma 530.3 -7 48

Figure 1: Breakdown by business segment of Mayne Pharma’s sales and grossmargin in its financial year ended 30 June 2018 (Source – Mayne)

MANUFACTURING/MERGERS & ACQUISITIONS

Italy’s Olon expandsthrough Indian plantItalian active pharmaceutical ingredient (API) supplier and contract

development and manufacturing organisation (CDMO) Olon hasexpanded its global footprint by striking a deal to buy an API facilityin Mahad, India, from Novartis. Describing the plant as “established andreputable”, Olon noted that it “provides a number of lifesaving medicinesto the Indian healthcare system and patients around the world”.

Milan-based Olon currently has seven manufacturing facilitiesin Italy, as well as one each in Spain and the US. All have beenauthorised by the US Food and Drug Administration (FDA).

“By acquiring a manufacturing base in India,” explained chiefexecutive Paolo Tubertini, “Olon will have the opportunity to accelerategrowth by adding new CDMO projects and to develop new genericproducts for the Indian market.” The plant comprised “a world-classmanufacturing facility and a dedicated team of experts”, he outlined.“No impact on jobs is planned and Olon intends to invest in the siteand pursue business-development opportunities to optimise the plant’sutilisation and expand its customer base,” the firm commented.

As part of the acquisition deal – for which no financial detailswere disclosed, and which is expected to be completed in early 2019“following a transition process” – Olon said it had struck a long-termsupply contract with Sandoz to continue supplying the Novartissubsidiary with products from Mahad.

“We look forward to a seamless transition for employees, patients,customers, partners and other stakeholders,” stated Tubertini. “Weare impressed by the know-how at the Mahad plant and intend toleverage their expertise to develop new opportunities in thepharmaceutical market, in India and elsewhere.”

Purchasing the Indian API plant forms part of a long-term strategicplan for Olon that also included acquiring Ricerca Biosciences’chemical division in Ohio, US, in mid-2017 (Generics bulletin, 16June 2017, page 4). It also involved the recent investment of morethan C10 million (US$11.6 million) to expand API manufacturinglines at the firm’s facility in Settimo Torinese, Italy, “a leading-edgeplant for development and production of APIs and advancedintermediates through microbial fermentation technology”.

Olon revealed that the next step in the firm’s three-year developmentplan would be moving to “the next target – to play an important rolein the manufacturing of biologics APIs”.

Commenting on the deal, Novartis said that “Olon, with its scaleand manufacturing expertise, has the capacity to contribute to theplant’s growth”. “It can take the site’s master plan to the next leveland best ensure the sustainability of local jobs and expertise whileguaranteeing the supply of lifesaving medicines to patients andcustomers.” Around 260 staff will be affected by the transfer.

Novartis told Generics bulletin the divestment was “part of atransformation strategy aimed at enabling the Anti-Infective & ChemicalOperations platform to create the next generation of API manufacturingfor our future Novartis portfolio by focusing on manufacturinginnovative medicines”, adding that it would also allow the firm to“increase competitiveness by accessing more cost-effective genericAPI alternatives for off-patent products”.

“By redefining our manufacturing requirements,” Novartisconcluded, “we have begun a journey to transform our sites, with eachsite exploring opportunities for the future – in some cases investment,in others divestment for longer-term viability, and in others completionof manufacturing and closure.” Gn [email protected]

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4 GENERICS bulletin 7 September 2018

COMPANY NEWS

[email protected]

Issue 367 l 7 September 2018

Director of Subscriptions: Val Davis Group Sales Manager: Rob Coulson

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Business Reporter: Grace Montgomery

Terms & Conditions: See www.generics-bulletin.com/subscribe.While due care has been taken to ensure the accuracy of information contained in this publication,the publisher makes no claim that it is free of error and disclaims any liability whatsoever for anydecisions or actions taken as a result of its contents.

Published by OTC Publications Ltd, 4 Poplar Road, Dorridge, Solihull B93 8DB, UK.Tel: +44 (0) 1564 777550 Fax: +44 (0) 1564 777524Company registered in England No 02765878.© OTC Publications Ltd. All rights reserved.Generics bulletin® is registered as a trademark in the European Community.Printed by Warwick Printing Company Ltd. ISSN 1742-0784

MANUFACTURING/FIRST-HALF RESULTS

Siegfried is preparingfor an FDA site visitSwiss contract manufacturer Siegfried is currently preparing for an

initial audit by the US Food and Drug Administration (FDA) of thebulk-drugs plant it has just built in Nantong, China. The Swiss groupexpects the US agency to visit the Nantong site, at which it says operationsare “proceeding according to schedule”, during the first half of next year.

Capacity utilisation at a sister facility in Zofingen, Switzerland,is “growing continually”, while the firm expects a logistics centre thatit is constructing at the Zofingen campus to be completed in the nearfuture, and 40 new laboratory workplaces are set to be “ready in thefourth quarter of 2018”. Furthermore, Siegfried recently acquired aproduction plant in Zofingen from its partner, Arena Pharmaceuticals.

Investment in laboratories linked to sterile filling of biologicalsubstances at the group’s injectables facility in Hamelin, Germany,is continuing, while Siegfried has finished increasing the floor spaceand capacity of its steriles site in Irvine, US.

Having built up critical mass for its Drug Substances bulk-drugsbusiness through capacity expansion and acquisitions, Siegfried seesachieving similar status for its Drug Products finished-dose division asthe “next step on its growth path”. The group intends to achieve thisgoal by improving its development set-up, promoting backward integrationand enhancing its technology base in areas such as micronisation,lyophilisation, spray-drying and handling highly-potent manufacturing.

In the first six months of this year, finished-dosage form salesthrough its Drug Products division climbed by 14.7% to SFr98.9million (US$102 million), accounting for just over a quarter of groupturnover that advanced by 8.0% as reported, and by 5.2% on a local-currency basis, to SFr377 million (see Figure 1).

The Swiss group strengthened its gross margin by 2.4 percentagepoints to 21.7%. And with both sales and marketing and research anddevelopment expenses almost static, Siegfried increased its operatingprofit by 26% to SFr37.7 million. G

Division First-half sales(SFr millions)

Change(%)

Proportionof total (%)

Drug Substances 278.3 +5.9 74

Drug Products 98.9 +14.7 26

Siegfried 377.2 +8.0 100

Figure 1: Breakdown by division of Siegfried’s sales in the first half of 2018(Source – Siegfried)

CONCORDIA INTERNATIONAL and its insurers have agreed topay US$13.9 million to settle shareholders’ class-action lawsuits.The proposed settlement – in which Concordia has not admittedthe plaintiffs’ accusations of misrepresenting and omitting materialfacts relating to the firm’s business practices, public filings andstatements – is subject to approval by Canadian courts in Ontarioand Quebec. The cases covered investors who had bought Concordiasecurities between 12 November 2015 and 11 August 2016.

BIOCAD has invested around RUB22 million (US$0.32 million)to build and equip a synthetic biology laboratory at the Siriuseducation centre in Sochi, Russia. The laboratory, which wasofficially opened by Russian president Vladimir Putin, will offertechnologies around bioinformatics, chemistry and molecular biology.

LUYE PHARMA said it “exceeded market expectations” by postinga 19.1% turnover rise to RMB2.20 billion (US$323 million) inthe first half of this year. The Chinese company said the transdermalpatch business that it bought from Acino at the end of 2016 was“running well”, while acquiring rights in 51 countries and territoriesto AstraZeneca’s quetiapine-based Seroquel and Seroquel XRantipsychotics had established a “solid foundation” for its pipelineproducts. Having raised its first-half research and developmentexpenditure by 57.7%, Luye said its LY03004 extended-releasemicrosphere formulation of risperidone had “entered its final stageof new drug application (NDA) in China and the US”. A similarformulation of rotigotine “has moved into the Phase III trials stage”,having been exempted from Phase II studies in China and the US.Meanwhile, the firm’s multi-day rivastigmine transdermal patcheshave “reached a critical stage of clinical development”.

NATCO PHARMA credited a 35% rise in Formulations turnover forits group turnover increasing by 28% to Rs5.75 billion (US$80.7million) in the Indian company’s financial first quarter ended 30June 2018. Finished-dose oncology drugs and profit-sharing dealsdrove the Formulations growth that more than outweighed a 22%slide in active pharmaceutical ingredient (API) turnover. Natco –which is particularly targeting Brazil and Canada for internationalexpansion (Generics bulletin, 13 July 2018, page 14) – almostdoubled its pre-tax profit to Rs2.32 billion.

CAMBREX saw its sales increase by 13% to US$152 million in thesecond quarter of 2018. Earnings before interest, tax, depreciationand amortisation (EBITDA) rose by 22% to US$52.2 million onlower personnel costs and selling, general and administrative costs.G

IN BRIEF

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COMPANY NEWSBUSINESS STRATEGY

Emcure’s Marcan hashead office in OttowaEmcure’s Canadian affiliate, Marcan Pharmaceuticals, is seeking to

“accommodate its growing business and increased product range”by inaugurating a new head office in Ottawa, Canada.

Having been co-founded in 2005 by Ottawa locals Atul and NavAggarwal, Marcan has since “steadily grown into a significant playerin the generic pharmaceutical industry”. In 2015, the Canadian companywas acquired by privately-owned Indian group Emcure, a move that“helped to expand Marcan’s manufacturing and research and developmentcapabilities, bringing Canadian expertise to Emcure’s global supplychain”. Emcure, Marcan pointed out, had invested millions of dollarsinto the Ottawa area.

“The new office inauguration is an important milestone in ourjourney over the past 13 years,” maintained president and chiefexecutive officer, Atul Aggarwal. “Since the acquisition of our companyby Emcure almost three years ago, there has been substantial investmentto bring new products to the Canadian market. Most of these productswill be first-to-market generics or products with limited sources thatwill not only save Canadian taxpayers millions of dollars, but alsoreduce the risk of drug shortages.”

Attending the inauguration were guests including HighCommissioner of India to Canada, Vikas Swarup and Jim Keon,president of the Canadian Generic Pharmaceutical Association (CGPA).Joining them were Emcure’s president of North America and Europe,Bill Marth, and president of corporate development and strategy,Vikas Thapar. G

BUSINESS STRATEGY/FIRST-QUARTER RESULTS

Kayaku lines up trastuzumabNippon Kayaku says “preparations for sales are underway” after

the trastuzumab biosimilar that the Japanese company licensesfrom Celltrion was listed in the country’s National Health Insurance(NHI) price list on 30 May this year. The partners had already obtaineda local marketing approval for Celltrion’s CT-P6 trastuzumab candidatein March this year (Generics bulletin, 30 March 2018, page 10).

Also through its collaboration with Celltrion, Kayaku currentlyhas the South Korean firm’s CT-P10 rituximab biosimilar undergoingPhase III clinical trials.

Focusing on increasing sales volumes for the infliximab biosimilarthat it launched in 2014 through the Celltrion tie-up enabled theJapanese firm to raise its biosimilars sales by 21.8% to around ¥800million (US$7.2 million) in its financial first quarter ended 30 June2018. The biosimilars advance all but offset a 3.6% slide in turnoverfrom generic cancer drugs to ¥5.1 billion that came despite growthfrom temozolomide tablets as NHI price cuts hit hard. Kayaku said ithad enjoyed stronger sales of active pharmaceutical ingredients (APIs)and from contract manufacturing.

Including exports, specialty chemicals and food technologyoperations, sales by the Pharmaceuticals segment – which is proceedingwith Phase II trials for its NK105 polymeric micelle formulation ofpaclitaxel – fell by 5.9% to ¥11.5 billion, as the segment’s operatingprofit nearly halved to ¥1.04 billion.

In its financial year ending in March 2019, Kayaku anticipatesPharmaceuticals sales edging up by 0.5% to ¥47.7 billion, but thesegment’s operating profit almost halving to ¥3.3 billion. G

BUSINESS STRATEGY/ANNUAL RESULTS

Adcock calls for risein South African SEPSouth Africa’s Adcock Ingram says it is “engaging constructively”

with the Pricing Committee of the country’s National Departmentof Health to see if any “short-term relief” will be available on thecountry’s single exit price (SEP), amidst “concern” over the recentfall in the value of the rand and rising costs at the company.

At the beginning of this year, South Africa’s health ministerallowed the SEP charged on a uniform basis to private, commercialcustomers to increase by a maximum of 1.26%, a rise that Adcockchief executive officer Andy Hall later described as “disappointing”(Generics bulletin, 2 March 2018, page 5).

“We’re not asking the government for anything that’s really outof line,” Hall insisted, in an interview with local broadcaster BusinessDay TV. “I think that if industry could get something between the1.26% that was given and consumer price index (CPI) that would bea good outcome for everyone, without prejudicing the consumer heavily,”he opined. Local health fund association HFA has expressed “strongopposition” to any further increase in the SEP this year (see page 12).

Sales rise by a tenthHall also warned that the depreciation of the rand “particularly in

the last six weeks” was going to “hurt” South Africa’s manufacturingindustry. Impinging Adcock further, he pointed out, the costs ofutilities in the country for manufacturers were rising “in the doubledigits”, compounded by a 7.5% rise in wages.

Adcock reported double-digit sales and profit increases for itsfinancial year ended 30 June 2018. Group sales increased by 10.2% toZAR6.54 billion (US$443 million) while “well controlled operatingexpenses” produced an operating profit that jumped by a fifth toZAR819 million.

For the firm’s Prescription business in South Africa, sales climbedby 15.5% to ZAR2.24 billion. This comprised 10.1% growth througha favourable product mix, “aided substantially” by the acquisition ofGenop; volume increases of 3.6% due to increased demand in the privatesector for the firm’s antiretrovirals; and an average price increase of1.8%. The business segment’s margin was flat at 10.7% year-on-year.

For products not subject to government regulations on price,Adcock’s board of directors has warned that trading conditions wereexpected to “remain difficult”, due to “constrained consumer spendingand high levels of unemployment” in South Africa. Gn [email protected]

Region Annual Sales(ZAR millions)

Change(%)

OperatingMargin (%)

Prescription 2,238 +15.5 10.7

OTC 1,989 +7.6 20.1

Hospital 1,348 +7.2 7.1

Consumer 687 -0.3 16.3

Other/Shared Services 77 +255 -1.3

Southern Africa 6,338 +10.1 13.3

Rest of Africa 223 +7.5 8.2

R&D India 19 +6.0 12.9

Eliminations -40 -7.7 -

Adcock Ingram 6,540 +10.2 12.51

1 Includes ZAR47 million of unallocated corporate expenses

Figure 1: Breakdown by business segment of Adcock Ingram’s turnover in itsfinancial year ended 30 June 2018 (Source – Adcock Ingram)

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COMPANY NEWS

9-11 Octobern CPhI Worldwide

Madrid, SpainCPhI Worldwide offers an exhibition and networking opportunities.Running alongside this event will be the ICSE, InnoPack, P-MECand Finished Dosage Formulation exhibitions.

Contact: UBM Information. Tel: +31 20 708 1637.E-mail: [email protected]. Website www.cphi.com.

22-23 Octobern Next Steps: Manufacturing &

Quality WorkshopMaryland, USAThis event, organised by the Association of Accessible Medicines(AAM), will provide information on manufacturing and qualitycomponents of generics and biosimilars businesses.

Contact: AAM. Tel: +1 202 249 7127.E-mail: [email protected]. Website www.accessiblemeds.org.

24-26 Octobern 21st APIC/CEFIC European Conference

Budapest, HungaryThis conference will discuss the latest developments in the fieldof GMP and regulatory compliance.

Contact: Concept Heidelberg. Tel: +49 6221 84 44-0.E-mail: [email protected]. Website www.api-conference.org.

29-30 Octobern World Biosimilar Congress

Basel, SwitzerlandThere will be networking receptions and lunches, an exhibitionand a conference included in this event.

Contact: Terrapinn. Tel: +44 207 092 1257.E-mail: [email protected]. Website www.terrapinn.com.

21 Novembern 2nd Value Added Medicines Conference

Brussels, BelgiumOrganised by Medicines for Europe, this one-day event will look atopportunities presented by value added medicines across the industry.

Contact: Lucia Romagnoli. Tel: +44 7562 876 873.E-mail: [email protected]. Register online atwww.medicinesforeurope.com/events.

26-27 Novembern EuroPLX 68

Athens, GreeceThis two-day meeting provides an opportunity to discuss andnegotiate agreements, development, in-licensing, marketing,promotion and distribution.

Contact: RauCon. Tel: +49 6221 426296 0.E-mail: [email protected]. Website: www.europlx.com.

EVENTS – October – November

9 October 2018

Sponsor,Join us!

[email protected] www.generics-bulletin.comCall: +44 1564 777550

Palacio Municipal de Congresos,Madrid, Spain

MANUFACTURING

Kyowa Hakko Bio ishit with FDA warningKyowa Hakko Kirin’s Kyowa Hakko Bio has responded to a

warning letter it has received from the US Food and DrugAdministration (FDA) for its Hofu manufacturing facility in Yamaguchi,Japan, concerning its active pharmaceutical ingredients (APIs).

In a statement acknowledging receipt of the warning letter, Kyowanoted that the observations included concerns about data integrity. “Weconfirm that there are no quality deficiencies in our products,” the firmmaintained, adding: “At this time, we are not instructed to recall ourproducts and/or suspend shipments due to this warning letter.”

The Hofu site forms part of Kyowa’s Yamaguchi ProductionCenter, along with the Ube facility. The two plants were integratedinto the Center in 2008 “for effective plant management”, and produce“a wide range of products from fine chemicals to feed additives andalcohol”, including amino acids and nucleic acids.

During a five-day inspection at the Hofu site in early September2017, the FDA identified “significant deviations” from current goodmanufacturing practice (cGMP). “Your firm performed retesting ormanipulated data after obtaining out-of-specification (OOS) or otherunacceptable results,” the agency stated.

An investigation found that a system suitability test (SST) wasnon-conforming and that “some data were manipulated to meet SSTspecification” for the high-performance liquid chromatography (HPLC)analysis of an undisclosed raw material. According to the agency,Kyowa attributed this to the company’s “lack of awareness of theseriousness” of cGMP deviations, and to an “environment where testdata could be easily manipulated”.

Deeming the firm’s controls over the HPLC systems “inadequate”,the FDA noted that these systems “did not have audit trail capabilityor audit trails enabled”. In addition, unique user names and passwordswere not required to perform HPLC activities. Kyowa said these hadnot been created so operators “could continue what previous operatorshad initiated”.

In the company’s annual product reviews, “unprotected Excelworksheets” were used to perform calculations and statistical evaluationsof production data, such as standard deviation and process capability.“These electronic files were not secured to prevent unauthorisedchanges, and have no change history,” the agency observed. “Your firm’slack of data control calls the reliability of your data into question.”

“You identified additional data integrity issues, but failed toprovide details regarding the corrective measures your firm hasimplemented,” the FDA continued. Similar deficiencies were cited ina warning letter issued to the site in September 2010, the agencynoted, and also at the Ube plant following an audit in September lastyear. “These repeated failures at multiple sites demonstrate thatexecutive management oversight and control over the manufactureof drugs is inadequate,” the FDA concluded.

The agency has requested that Kyowa provide a thoroughassessment of the overall system for investigating deviations,discrepancies, OOS results, complaints and other failures; a review ofcontrols and procedures for electronic data generated from all laboratoryequipment; and a management strategy detailing the firm’s globalcorrective action and preventive action plan.

“Until you correct all deviations completely and we confirmyour compliance with cGMP,” the agency warned, “the FDA maywithhold approval of any new applications or supplements listingyour firm as a drug manufacturer.” Gn [email protected]

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BUSINESS STRATEGY/ANNUAL RESULTS

Lannett makes plansfor JSP deal finishingLannett “is re-assessing its overall business strategies” in preparation

for its key distribution agreement with Jerome StevensPharmaceuticals (JSP) expiring in March 2019. Predominantly coveringlevothyroxine tablets, the deal represents more than a third of the USgroup’s sales. Eschewing a renewal agreement with Lannett forlevothyroxine, digoxin and butalital/aspirin/codeine/caffeine, JSPrecently signed a deal for levothyroxine with rival Amneal.

“Management is continuing to finalise plans to offset the impact ofthe loss on a short- and long-term basis,” the US-based player admits.These plans currently include an emphasis on reducing cost of sales,research and development and selling, general and administrativeexpenses; continuing to accelerate new product launches; increasingthe level of strategic partnerships; and reducing capital expenditures.

“On the revenue side, we are engaged in an ongoing process toanalyse our investment strategy to develop what we believe to bestrong, risk-adjusted returns and resulting cash flows,” chief executiveofficer Timothy Crew revealed. “On the expense side, we have targetedsubstantial cost savings across all expense lines compared to ourearlier budgets.”

Summarising ongoing efforts to be more efficient, raise money andreduce costs, Crew said Lannett’s primary plant in Seymour, Indiana,had “significantly increased its output by more than 50% comparingfiscal 2017 to fiscal 2018”, while Lannett had also recently sold offtwo unused buildings in Philadelphia for around US$14 million.

Furthermore, Crew pointed to Lannett’s previously-announcedrestructuring and cost-reduction plan for its Cody Laboratories activepharmaceutical ingredients (APIs) manufacturing subsidiary, “significantlyreducing operating overheads”. “We have also begun the consolidationof our Philadelphia distribution site,” noted Crew, “transferring thatfunction to our primary distribution centre in Seymour.”

On the commercial side, Crew pointed to eight product launchessince 1 January, noting that these were expected to contribute morethan US$50 million to turnover in Lannett’s current financial yearended 30 June 2019. “Given our large pool of approved but not yetlaunched products and filed drug product applications awaiting approvalat the US Food and Drug Administration (FDA), our goal is tocontinue this recent rate of launching products,” Crew noted.

In Lannett’s financial year ended 30 June 2018, sales oflevothyroxine shooting up by more than two-fifths to US$246 milliondrove 8.1% sales growth to US$685 million. For the thyroid deficiencytreatment, this comprised 30% of volume growth on an 11% pricehike, as Lannett benefitted from a supply disruption for a competitor.

Overall, Lannett enjoyed volume growth of US$110 millionduring its 2018 financial year, with US$62.2 million worth of valueeroded through price declines. Cutting its operating expenses by morethan a quarter to US$159 million caused Lannett’s operating profit tojump up by half to US$130 million, on those higher sales.

In light of its sizeable debt obligations, Lannett stressed that“continued progression on our base business from new product launches,combined with cost containments, will ensure that we have sufficientcash flow from operations to provide liquidity to fund our currentobligations, projected working capital requirements and capitalexpenditures through this fiscal year”. The company’s long-term debtas of 30 June stood at US$897 million, while the firm had cash andcash equivalents of US$98.6 million. Lannett’s market capitalisationwas around US$20 million as Generics bulletin went to press. Gn [email protected]

BUSINESS STRATEGY/FIRST-HALF RESULTS

ScinoPharm chasesopportunities in USHigh-potency active pharmaceutical ingredient (API) producer

ScinoPharm is looking to strategic alliances that will enable it toforward-integrate and capture US finished-dose opportunities throughparagraph IV patent challenges and 505(b)(2) hybrid applications. Atthe same time, the Taiwanese company intends to target difficult-to-make peptide APIs while offering an “integrated service from API toformulation for niche injectables” alongside fill-and-finish servicesfor biological drugs.

In March this year, ScinoPharm secured US approval for its firstoncology abbreviated new drug application (ANDA), decitabine,through a co-development deal with Nichi-Iko’s Sagent.

In October last year, the Taiwanese firm filed an ANDA forregadenoson with Nanjing King Friend, while another ANDA with aparagraph IV challenge for an undisclosed imaging agent is expectedto result in a 2021 launch. The company’s first self-developed ANDAwas for fondaparinux, while its 505(b)(2) pipeline includes leuprolidewith Foresee and an undisclosed lung-cancer drug with a US partner.

Half of the 26 APIs that ScinoPharm has launched to date are inthe oncology arena, with another six for central nervous system (CNS)disorders and four for treating infectious diseases. However, thecompany says it has another 22 oncology bulk drugs in its pipeline.

In the first half of 2018, ScinoPharm raised its sales by 4% toNT$1.85 billion (US$60.1 million). Four-fifths came from generics. G

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COMPANY NEWSBUSINESS STRATEGY

Pfizer urges action onbiologics denigrationPfizer has filed a citizen petition asking the US Food and Drug

Administration (FDA) to issue guidance deterring innovatorcompanies from suggesting that biosimilars are not as safe andeffective as reference biologics.

In its petition, Pfizer requests that the agency publish a documentdescribing the types of sponsor communications about referenceproducts and biosimilars – including interchangeable biologics – thatwould be false or misleading. It contends inappropriate messagesinclude those that suggest there is a clinical difference betweenreference products and biosimilars, or that a patient should not beswitched to a biosimilar. The company also asks that the guidanceclarify that biosimilar sponsors may communicate clinical trial dataabout their products, even if it is not in labelling.

“For the few biosimilars that have both obtained marketingapproval and achieved commercial launch, market acceptance, ingeneral, has been much slower than anticipated,” the petition states.“We believe that a major factor contributing to this slow uptake is alack of market confidence in biosimilars resulting from the efforts ofcertain reference product sponsors to disseminate false and misleadinginformation that casts doubt about the safety and efficacy of biosimilarsin the minds of patients and prescribers.”

Pfizer has recently taken a lead in trying to take down barriersbrand companies have put up to protect their blockbuster biologics,including filing a suit against Johnson & Johnson over exclusionarycontracts with payers that block biosimilars. The petition cites examplesof communications it regards as misleading, including a Genentech‘Examine Biosimilars’ website, an Amgen tweet and YouTube video,and a Janssen patient brochure for Remicade (infliximab).

Pfizer notes that the Biologics Price Competition and InnovationAct (BPCIA) “explicitly states that a biosimilar is highly similar tothe reference product but has the same mechanism of action, meaningthat a biosimilar works in the same way as the reference product”. ButJanssen’s materials “confuse this distinction by stating that infliximabbiosimilars work in a ‘similar’ way to Remicade”.

The petition says Amgen includes a similar message in a YouTubevideo stating that a switch “carries risks, given that no two biologicmedicines are identical, and thus can behave differently in the body”.Switching drugs “is not a good idea if your medicine is working foryou”, the video adds.

Pfizer also cites a tweet by Amgen Biosimilars that says “Biologicsor biosimilars? It’s not just apples to apples. While biosimilars maybe highly similar to their biologic reference products, there’s still achance that patients may react differently.”

The petition also points to Genentech’s ‘Examine Biosimilars’website, which says the FDA requires a biosimilar to be highly similar,but not identical to the reference product. The petition says the websitefails to state that an approved biosimilar must have no clinicallymeaningful differences from the reference product.

In response to the petition, Amgen said it was committed toeducational communication of factual, balanced information regardingbiosimilars and their use, and believes such communications helpbuild the confidence necessary to ensure biosimilar uptake. “As amanufacturer of both novel biologics and biosimilar medicines, Amgenis fully committed to the success of the biosimilars market and toour biosimilars portfolio of 10 biosimilars which target some of themost complex and important biologics medicines,” the firm stated. Gn Presented in conjunction with our sister publication, Pink Sheet

MANUFACTURING

Four Indian firms getplant nods from FDAAraft of US approvals for Indian generics manufacturing facilities

have been received by key industry players, as Dr Reddy’s, JBChemicals & Pharmaceuticals, Lupin and Zydus Cadila all receivedUS Food and Drug Administration (FDA) endorsements for theirmanufacturing facilities.

Dr Reddy’s said its ‘SEZ’ active pharmaceutical ingredient (API)plant in Srikakulam, Andhra Pradesh, had received an establishmentinspection report (EIR) from the FDA, closing out an audit that tookplace earlier this year and was completed with no observations(Generics bulletin, 8 June 2018, page 7).

At the time, Dr Reddy’s noted that another of its API facilitiesat the Srikakulam site was subject to an FDA warning letter, and itwas “not yet clear” whether that facility would require a re-inspectionin order to be brought back to compliance (Generics bulletin, 25 May2018, page 3). The firm is also currently working to resolve a warningletter at its oncology site in Duvvada, Andhra Pradesh (Genericsbulletin, 3 August 2018, page 3).

JB Chemicals & Pharmaceuticals noted that it had passed a“successful FDA inspection of our solid oral dosage forms formulationsmanufacturing facility at Panoli, Gujarat” after being inspected from20-24 August. The US regulator issued “two minor proceduralobservations” as part of the audit, JB noted, following a similar verdictearlier this year at an API site (Generics bulletin, 18 May 2018, page 6).

“These observations do not impact the continuity of the firm’sbusiness, and the company will continue its manufacturing activitiesin a current good manufacturing practice (cGMP) compliant manner,”JB stated. It pledged to “address these observations in the next 30 days”.

JB explosion takes tollJB – which saw its sales rise by 28.9% to Rs3.66 billion (US$51.4

million) in its financial first quarter ended 30 June 2018 – warnedthat a recent reactor explosion at the Panoli API site in early July(Generics bulletin, 13 July 2018, page 5) had affected four out ofeight plants at the unit.

It would take “around nine to 10 months” for the affected plants tobegin commercial manufacturing again, with a Rs50 million impacton sales and a further Rs20 million cost for procuring certain APIsfrom third parties JB said, adding that the affected assets were “fullycovered by insurance”.

Lupin said it had received an EIR from the FDA following asuccessful inspection of its Nagpur oral-solid manufacturing facility bythe agency in May (Generics bulletin, 25 May 2018, page 5). “Thesuccessful completion of the Nagpur facility inspection is a positivedevelopment,” commented Lupin’s managing director Nilesh Gupta,“as we continue our journey to meet and exceed internationalregulatory standards.”

The firm recently noted that it was continuing to work towardsresolving an outstanding FDA warning letter against its Goa andIndore Unit II manufacturing sites and has now sent a “final warningletter response” to the agency (Generics bulletin, 31 August 2018,page 11). The two sites have already been cleared by UK and Canadianregulators respectively (Generics bulletin, 27 July 2018, page 6).

And Zydus Cadila said its biologics manufacturing facility atthe Zydus Biotech park in Ahmedabad had been inspected by theFDA from 14-24 August, resulting in “no ‘Form 483’ observation”being issued by the agency. Gn [email protected]

Gen 7-9-18 Pgs.1-24.indd 9 04/09/2018 16:42

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MARKET NEWSPRICING & REIMBURSEMENT

SA scheme opposes arise in country’s SEPSouth African body the Health Funders Association (HFA), which

represents local stakeholders involved in funding private healthcare,has announced strong opposition to “any interim increase in medicinecosts this year”. This comes in the wake of lobbying of governmentby industry for a further increase in the 2018 single exit price (SEP).

SEPs charged on a uniform basis to private, commercial customerswere allowed to increase by a maximum of 1.26% in 2018 under alegislative order signed at the beginning of the year (Generics bulletin,19 January 2018, page 8). South African inflation as measured by theconsumer price index (CPI) rose from 4.38% in June to 5.05% in July.

“According to claims data from HFA member schemes, if aninterim SEP increase to the level of CPI were to be allowed, as proposedby the pharmaceutical industry, medical schemes would incur anadditional cost of at least ZAR260 million (US$17.8 million) over theremaining four months of 2018, considering projected volume growth,”the association warned. “The annualised impact of this increase wouldbe over ZAR1 billion in 2019, even before next year’s SEP adjustment.”

Adcock Ingram has confirmed that it is engaging with governmentfor an increase in the SEP, against the backdrop of a recent sharp fallin the value of the South African rand and rising inflation (see page 5).

“The inflation rate of medicine is already considerably higherthan the negotiated SEP adjustment,” the HFA argues, noting that costinflation of medicine was also driven by volume growth. Data providedby its member organisations, the HFA insisted, showed that despitethis year’s regulated SEP increase of 1.26%, during the first half of2018 overall cost inflation for chronic medicines had increased byup to 6%, and up to 8% in the case of cancer medicines.

The HFA added that rising costs had been compounded by thisyear’s value-added tax (VAT) increase, from 14% to 15%, “which wasnot factored into medical scheme budgets for 2018”. This factor alonehad imposed an additional ZAR875 million unbudgeted expenditureon the medical aid industry in the current financial cycle, it said.“Nonetheless, the vast majority of medical schemes opted to find waysto absorb this unbudgeted cost within their already stretched operatingbudgets, rather than seek to introduce interim contribution increasesfrom members who are already under significant financial strain.” G

REGULATORY AFFAIRS

EU task force worksto alleviate shortagesWork-sharing for generics and biosimilars, the UK’s ‘Brexit’ exit

from the European Union (EU), paediatric formulations andmultilingual packages are among the topics addressed in a newlypublished action plan on improving the availability of medicinesauthorised in the EU. On 8-9 November, the task force – which willmeet by teleconference four times per year – plans to hold a multi-stakeholder workshop on drug availability to inform its activities throughcontributions from patients, healthcare professionals, wholesalers anddistributors, academics and regulators, as well as from industry.

An accompanying two-year work program published jointly bythe European Medicines Agency (EMA) and heads of medicinesagencies (HMA) in the EU claims that easing the approval of genericsand biosimilars through joint evaluations, work-sharing and shortenedtimetables has already been completed. “This will facilitate marketentry for these medicines and help to increase users’ access tomedicines,” it maintains.

Facilitating approval and marketing of medicines using theexisting regulatory framework, such as through work sharing andshorter timetables, is one of five key priorities for the task force ofnational and EMA regulators, along with the European Commission,as it seeks to “develop and co-ordinate actions for better prevention,identification, management of and communication on issues that canaffect the availability of medicines”. The other four priorities are:preventing and managing shortages caused by disruptions in the supplychain, including by developing guidance for industry on reportingshortages; encouraging industry best practices; improving bestpractices and information-sharing between EU regulatory agencies;and fostering collaboration and communication between stakeholdersand to the public.

Within the first priority, covering marketing authorisations, thetask force intends by the end of this year to identify potential supplyissues due to the UK’s withdrawal from the EU. It aims to providepractical guidance on implementing regulatory changes requiredfollowing Brexit, such as changing the reference member state, tomonitor how such changes are implemented and to minimise thedisruption to medicines supplies that could cause shortages.

On Brexit, the agencies acknowledge that this is “likely toaffect the availability of medicines in the UK”. The task force, theyinsist, will provide “a platform to facilitate and co-ordinate actionsbetween member states, the EMA and the European Commission”.

Action to be completed by the end of 2019 includes acceleratingmutual-recognition procedures to “extend marketing authorisationsto countries where companies would not normally seek marketingauthorisation”. And by the fourth quarter of 2020, the task force hasset goals such as improving the exchange of information on whichpaediatric formulations are available, reviewing drug-recall procedures,and promoting multilingual packaging to allow easier transfer ofmedicines, particularly to smaller markets.

Supply-chain steps planned for this year include developing aconcept of reportable shortages and offering industry guidance onreporting. Communication targets are scheduled by mid-2019.

The program – which describes medicines unavailability as “anarea of great concern” – is accompanied by an EU regulatory networkreflection paper finalised by the EMA and HMA in late-2016. This coversmany of the same issues around marketing of authorised medicines,supply-chain disruption, communication, governance and reporting. Gn [email protected]

INTELLECTUAL PROPERTY

Canada toughens up listingCanadian originators submitted a five-year record number of patent

lists to be linked against drugs in the country’s patent register inthe 12 months ended 31 March 2018. But the number of patent listsadded to the register over the same period shrank by just over a fifthto 606, despite the 8% rise to 898 in patent lists received, according to astatistical report on data protection and the country’s Patented Medicines(Notice of Compliance), or PMNOC, patent-linkage regulations.

A 62% leap to 120 in the number of patient-listing rejectionssuggests a more stringent oversight of the register by the Health Canadaagency, although one drug has 16 separate patents listed against it.Listed patents can be used to block generic approvals, as can eight-yeardata protection that is also subject to a six-month paediatric extension.The report says just over a fifth of medicines – eight of 37 – addedto Canada’s register of innovative drugs in the 2017/2018 financialyear benefitted from a paediatric extension. G

Gen 7-9-18 Pgs.1-24.indd 12 04/09/2018 16:42


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REGULATORY AFFAIRS

France adds three tosimilar biologics listAvastin (bevacizumab), Humalog (insulin lispro) and Herceptin

(trastuzumab) have been added to France’s list of similar biologicsas reference brands for newly-created similarity groups by localmedicines agency ANSM. They add a further three groups to the 11created when ANSM introduced the list last year (Generics bulletin,10 November 2017, page 11), taking the full list to 14 referencegroups covering 45 biosimilar brands.

Alongside Roche’s Avastin, Amgen’s Mvasi bevacizumabbiosimilar has been listed. Meanwhile, Sanofi’s biosimilar insulin lisprohas been included next to Eli Lilly’s Humalog. And both Celltrion’sHerzuma and Samsung Bioepis’ Ontruzant have been listed astrastuzumab biosimilars in the same group as Roche’s Herceptinoriginal. Herceptin 600mg solution for subcutaneous injection doesnot have an associated biosimilar, the listing notes.

Biogaran has recently claimed the first French launch of biosimilartrastuzumab through a marketing tie-up with Celltrion for the Koreancompany’s Herzuma (see page 17).

At the same time as adding the three new groups, ANSM hasexpanded an existing group with Sanofi’s own Lovenox (enoxaparin)as the reference brand by adding Rovi’s Becat and Crusia, as well asSanofi’s own biosimilar. And Sandoz’ Zessly (infliximab) was listedas similar to Janssen’s Remicade, in a group that also includes SamsungBioepis’ Flixabi, Pfizer’s Inflectra and Biogaran’s Remsima. G

REGULATORY AFFAIRS

BGMA seeks clarityon reference productsClarity over whether drugs that have been centrally authorised in

Europe will convert into reference products for the purposes ofUK generic marketing authorisations after the country leaves theEuropean Union (EU) on 29 March 2019 is being sought by theBritish Generic Manufacturers Association (BGMA).

Following the publication of technical notices detailing contingencyplans in the event of no ‘Brexit’ deal being reached between UK andEU negotiators (Generics bulletin, 31 August 2018, page 1), theBGMA’s director general, Warwick Smith, said the notices “makeclear that the details of the conversion of centralised proceduremarketing authorisations into UK marketing authorisations on 29March will be subject to consultation”.

“We infer that these products will then legally become referenceproducts that have been authorised in the UK,” Smith stated. “Wetherefore expect that it will be possible for generic UK marketingauthorisation applications to be made based on these reference products.”

“We shall, however, take this up with the UK Medicine andHealthcare Products Regulatory Agency (MHRA) as part of theconsultation to confirm the position,” Smith indicated. “It is clearlyin no-one’s interests for the supply of new generics to be barred ordelayed.” The BGMA has previously called for a deal between UKand EU negotiators as “the only way to ensure that the supply ofmedicines is not disrupted” in the UK. G

Gen 7-9-18 Pgs.1-24.indd 13 04/09/2018 16:42

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PRODUCT NEWSCARDIOVASCULAR DRUGS

FDA examines causeof valsartan impurityThe US Food and Drug Administration (FDA) says a “major

operation” is underway to investigate and address the “troublingfinding” of a toxic impurity in some generic versions of valsartanthat could cause cancer, leading the agency to also test all drugs invalsartan’s therapeutic class for traces of the toxic material.

The mandate of the FDA’s “dedicated task force of experts” isto “oversee the investigation and track new developments andinformation coming in from valsartan manufacturers”, the FDA noted.“This multidisciplinary team of chemists, toxicologists, medicaldoctors, pharmacists, investigators, communication specialists, andanalytical lab staff coordinates across the FDA, and acts on thenewest available information.”

Valsartan finished-dose products in the US using activepharmaceutical ingredient (API) made by Chinese manufacturers ZhejiangTianyu was found to contain low levels of N-nitrosodimethylamine(NDMA), classified as a probable human carcinogen, leading the FDAto issue recalls (Generics bulletin, 27 July 2018, page 17). Regulatorsacross the globe, including in Canada and Europe, have also acted.

Referring to the impurity found in Zhejiang Huahai’s valsartanAPI, the FDA said it believed the problem occurred “through a specificsequence of steps in the manufacturing process,” but was “still not100% sure this is the root cause.” Full understanding would require“correlation of multiple test results from valsartan APIs made bydifferent processes with the various process steps used by differentmanufacturers or at different times”, the FDA said.

“Based on our analyses of the manufacturing processes, we arenow testing all the products in the angiotensin II receptor blocker(ARB) class to determine if they contain NDMA,” the agency revealed.“In some cases, the steps in the synthesis of other ARBs can havesimilarities to the synthesis of valsartan. These tests will continueuntil we identify all products that may contain NDMA in the ARBclass, and they are no longer available in the US.”

The FDA also warned that, because its investigation was continuing,more manufacturers may discover that their valsartan products containNDMA and take steps to voluntarily recall them. “The initial recallhas expanded to now include five manufacturers and other companieswho repackage those products under a different name,” the FDA noted. G

PRICING & REIMBURSEMENT

Australia’s PBS adds ApotexApotex has had several products listed for reimbursement on

Australia’s Pharmaceutical Benefits Schedule (PBS) from 1September, including eight strengths of amlodipine/atorvastatin tablets.The six highest strengths – 5mg/40mg to 10mg/80mg – join Pfizer’sCaduet original and Alphapharm’s generic, while the 5mg/10mg and5mg/20mg strengths compete only with the Alphapharm product.

The Canadian firm also received listings for gliclazide 80mg tabletsand glimepiride 1mg, 2mg, 3mg and 4mg tablets. Strides’ Arrow Pharma,which is set to merge with Apotex’ local business, listed two brandedgenerics, Tacrograf (tacrolimus) 500µg,1mg and 5mg capsules andPryzex (olanzapine) 15mg and 30mg orally disintegrating tablets.

Other firms receiving listings onto the PBS included Aspen Pharmafor its codeine 30mg tablets and Wockhardt for the Indian firm’stobramycin 300mg/5ml inhalation solution. G

SANDOZ has been sued by AbbVie in a New Jersey district courtfor alleged infringement of US patents 9,187,559 and 9,750,808protecting Humira (adalimumab). The patents are entitled respectively‘Multiple-variable dose regimen for treating idiopathic inflammatorybowel disease’ and ‘Formulation of human antibodies for treatingTNF-alpha associated disorders’. In the suit, the originator allegesthat Sandoz, after losing six inter partes proceedings on Humirapatents to AbbVie, has “elected to put off confronting the vastmajority of AbbVie’s patents for another day” by choosing to litigatenow only two of the 84 patents that AbbVie had identified asrelevant. All 84 patents are listed in the suit. AbbVie noted that itcould seek legal relief on the other 82 patents once Sandoz gave180-day notice of commercial marketing. In January this year, Sandozsaid the US Food and Drug Administration had accepted for filing thefirm’s abbreviated biologic license application (aBLA) for its GP2017adalimumab candidate (Generics bulletin, 19 January 2018, page 10).

MARCAN PHARMACEUTICALS has made midodrinehydrochloride 2.5mg and 5mg tablets available in Canada. Thealternative to Amatine comes in 100-count packs.

PHARMAC – New Zealand’s Pharmaceutical Management Agency –is proposing to make Mylan’s Logem (lamotrigine) 25mg, 50mg,100mg dispersible tablets the only reimbursed brand of the epilepsytreatment in community and hospital settings from 1 May 2019. Themove, which is open for consultation until 26 September, wouldeffectively delist from funding both GlaxoSmithKline’s Lamictaloriginal and Teva’s Arrow-Lamotrigine generic. Lamictal andArrow-Lamotrigine 2mg and 5mg dispersible tablets would remainfully funded. From 1 July 2019, Mylan’s Aurorix (moclobemide)150mg and 300mg tablets are to attain sole subsidised supply statusin New Zealand, followed from 1 August 2019 by Pfizer’s Nivestim(filgrastim) 300µg/0.5ml and 480µg/0.5ml pre-filled syringes. Theywill displace Apotex’ Apo-Moclobemide and Sandoz’ Zarzio.

MYLAN this year expects to pay around US$240 million of aUS$463 million purchase of global rights to an undisclosedcommercialised product. Having struck the deal on 30 July, Mylanexpects to close the transaction later this year.

AMNEAL has struck a five-year US supply and distribution deal withDaiichi Sankyo’s American Regent “for the only preservative-freegeneric alternative to Makena (hydroxyprogesterone caproate)250mg/ml injection”. Amneal will distribute the drug for reducing therisk of pre-term birth to retail consortia, with American Regentretaining rights to hospital and specialty channels. Amneal has alsosecured US approvals for generic Temovate (clobetasol propionate)0.05% ointment and Lidex (fluocinonide) 0.05%, and has justlaunched a rival to Lodine (etodolac) 400mg and 500mg tablets.

BRECKENRIDGE PHARMACEUTICAL is to market injectableazacitidine in the US through a “tripartite agreement” that will seeNatco Pharma provide manufacturing technology for Panacea Biotecto make the 100mg vials at its facility in Baddi, India. Natco alreadyholds US approval for the generic version of Celgene’s Vidazaleukaemia treatment.

US GENERICS PLAYERS including Accord, Amneal, Apotex,Aurobindo, Mylan, Sun Pharma, Teva and Zydus Cadila have failedto persuade the US Court of Appeals to hold a rehearing en banc ofthe court’s split decision to uphold US patent RE38,551 protectingUCB’s Vimpat (lacosamide) until 17 March 2022 (Genericsbulletin, 1 June 2018, page 11). G

IN BRIEF

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PRODUCT NEWSERYTHROPOIESIS-STIMULATING AGENTS

Sandoz’ Binocrit willreplace Eprex in NZSandoz’ Binocrit (epoetin alfta) will soon become the only subsidised

version of the erythropoiesis-stimulating agent in New Zealand,according to plans set out by local pharmaceutical management agency,Pharmac. The decision to stop funding Janssen’s Eprex brandedequivalent from next year and reimburse Sandoz’ biosimilar exclusivelyis aimed at cutting spending on the drug and ensuring continuedsupply for a period of three years.

Eprex, which stimulates the production of red blood cells, iscurrently fully subsidised, subject to special authority and hospitalrestrictions, as a treatment for chronic renal failure and myelodysplasia.The subsidy price ranges from NZ$48.00 (US$32) for a 1,000IU/0.5mlsyringe to NZ$263.45 for a 40,000IU/1ml syringe.

Under the proposal, the funded brand would change from Eprexto Binocrit after a transition period lasting from 1 February 2019 to1 July 2019. “From the end of the transition period, Binocrit would bethe only funded brand in both the community and hospital settings,”Pharmac says, meaning that patients using Eprex “would need tochange to Binocrit to keep accessing a funded treatment”.

The agency has already entered into a provisional agreementwith Sandoz’ parent company Novartis for the supply of epoetin alfa,and is now running a consultation on the proposal, with commentsdue by 10 September. The feedback, it says, will allow it to decidewhether this agreement should be confirmed. If it is, the price andsubsidy level for Binocrit will be notified, and a confidential rebatewill apply so that the net price to Pharmac is reduced.

Binocrit would be awarded hospital supply status for epoetininjections in district health board (DHB) hospitals for a three-yearperiod from 1 April 2019 to 30 June 2022. This means Binocrit wouldbe the only brand of epoetin available in DHB hospitals, subject to a1% discretionary variant limit, meaning that 99% of the total volumeof erythropoietin purchased by DHB hospitals would have to be Binocrit.

Janssen plans Pharmac responseFor community pharmacies, Binocrit would be awarded sole

subsidised supply status for epoetin for the same period. Once Binocritis listed on the Pharmaceutical Schedule, pharmacies may continueto dispense and claim for any listed brand for the duration of thetransition period, after which only Binocrit will be reimbursed.

Janssen Australia and New Zealand told sister publication PinkSheet that “we don’t have a specific comment to make on the PharmacEprex proposal and process”, but confirmed that the company “willbe responding to the consultation”.

The rationale for changing the funded brand was outlined byPharmac in a request for proposals (RFP) to supply epoetin, publishedin May this year, which noted that the agency was “aware of a numberof short- and long-acting products registered in New Zealand or availableoverseas”. As a result of this competition, the RFP aimed to “reducethe total expenditure in the erythropoietin market” and to “securesupplies of funded short-acting erythropoietin for another three years.”

The RFP said Pharmac would consider “any proposal fromsuppliers of erythropoietin,” and would accept a range of suggestionsincluding sole supply, rebates or other risk-sharing deals. The agencyalso wanted to know whether funded access to a long-actingerythropoietin such as darbepoetin would be possible within theavailable budget. If so, it said it would “progress funding and securesupply of a long-acting erythropoietin via the RFP process”. Gn Presented in conjunction with our sister publication, Pink Sheet

AUTOIMMUNE DISEASES TREATMENTS

Celltrion aims to fileRemsima SC productCelltrion plans to file a marketing authorisation application with

the European Medicines Agency (EMA) by the end of this yearfor the firm’s novel subcutaneous (SC) formulation of its Remsima(infliximab) biosimilar, after completing a Phase III clinical trial forthe product candidate.

Preparation for filing the application was “now in the final stage”,the Korean firm noted, with Celltrion set to complete clinical analysisof the Phase III data “soon”. Celltrion underlined that it was developingthe more convenient Remsima SC “in a bid to obtain its competitivenessin the TNF-α inhibitor market through a ‘twin-track’ strategytogether with the existing intravenous (IV) formulation of Remsima”.

To this end the firm is also developing a high-concentration,CT-P17 biosimilar formulation of AbbVie’s Humira (adalimumab),recently announcing the start of European Phase I and Phase IIIclinical trials (Generics bulletin, 10 August 2018, page 15).

Earlier this year, Celltrion presented clinical data showing thatRemsima SC was comparable in terms of efficacy and safety withthe firm’s existing IV formulation of the monoclonal antibody up toweek 30 in patients with active Crohn’s disease (Generics bulletin,15 June 2018, page 11). An open-label, randomised, controlled, phase Istudy conducted by Celltrion had aimed to find the “optimal dose” ofsubcutaneous CT-P13, Remsima’s development name, by establishingpharmacokinetic (PK) comparability to CT-P13 IV dosing. G

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PRODUCT NEWS

Up to the minute live retail market pricing is availablefor the UK and Eire on Wavedata Live at wavedata.net.

Alternatively, contact Charles Joynson at WaveData Limited, UK.Tel: +44 (0)1702 425125. E-mail: [email protected].

UK rises lead to concessionsSteep average UK trade price rises for molecules such as

propranolol, ramipril and risperidone provoked the country’sDepartment of Health and Social Care (DHSC) to grant priceconcessions to pharmacists for more than 20 molecules across over50 separate presentations in August, according to the latest figuresfrom market researcher WaveData and the UK’s PharmaceuticalServices Negotiating Committee (PSNC).

Comparing UK trade prices to independent pharmacists in theperiod 1-31 August 2018 to the previous month, WaveDatareported that propranolol 80mg tablets in 56-count packs saw theiraverage trade price more than treble to £4.21 (US$5.43), while28-count packs of 10mg and 40mg tablets saw leaps of 105% to£4.26 and 91% to £4.40 respectively. DHSC concession pricesof £2.70 for the 10mg strength and £2.64 for the 40mg presentationsfell well short of these averages, which were calculated from atleast 32 data points.

Ramipril 10mg, 5mg and 2.5mg tablets in 28-count packs sawrespective rises of 74% to £4.48, 71% to £5.03 and 65% to £4.50.DHSC concessions of £3.20, £4.20 and £3.90 all again fell short.

And risperidone in several multiple presentations continuedto experience average price rises (Generics bulletin, 31 August2018, page 19) as high as 197% for 60 risperidone 2mg tablets,with concessions granted for five different presentations. G

PRICE WATCH ....... UK

ONCOLOGY DRUGS

Biogaran is first withFrench trastuzumabFrance’s Biogaran has claimed the first launch of a trastuzumab

biosimilar in the country with its introduction of Herzuma 150mgpowder for solution through a marketing deal with South Korea’sCelltrion. “A second presentation of a 420mg vial of Herzuma willbe available shortly,” the French firm added.

Insisting that the launch reinforced the Servier subsidiary’s statusas “number one in hospital biosimilars” in France – based on GERSfigures to June 2018 – Biogaran noted that the introduction oftrastuzumab followed successful first-to-market launches of Remsima(infliximab) in 2015 (Generics bulletin, 27 March 2015, page 17)and Truxima (rituximab) in September 2017 (Generics bulletin,15 September 2017, page 13). Almost a third of French infliximabpatients were now treated with Remsima and almost 60% of rituximabpatients with Truxima, the firm claimed.

“We are pleased to provide pharmacists and hospital healthcareprofessionals with our biosimilar medicines,” stated Biogaran presidentPascal Brière. Referring to the supply of biosimilars as the firm’s“primary vocation”, Brière said the firm’s portfolio of biosimilarswould “give a larger number of patients access to new innovativeand costly treatments, allowing our healthcare system to unlockcollective savings without any concession on quality or patient care”.

A fourth biosimilar would be introduced in the second half of theyear, Biogaran added, suggesting that this would again be a first-to-market launch.

RESPIRATORY DRUGS

Glenmark inks a dealfor Spiriva in EuropeGlenmark is aiming to bolster its burgeoning respiratory presence

in Europe by signing an exclusive licensing and marketingagreement with an undisclosed third party for a generic of BoehringerIngelheim’s Spiriva Handihaler (tiotropium bromide) dry-powderinhaler in Western European markets.

No financial details were disclosed of the deal for the generictreatment of chronic obstructive pulmonary disease (COPD). QuotingIqvia data, Glenmark said the German originator’s brand achievedsales of US$724 million in the European Union (EU) in the 12 monthsended March 2018.

Six-month paediatric extensions to supplementary protectioncertificates (SPCs) linked to European molecule patent EP0,418,716protecting Spiriva expired in major EU member states in March 2016,including France, Germany, Italy, Poland, Spain and the UK (Genericsbulletin, 25 March 2016, page 8).

A further European patent, EP1,379,220, continues to shieldSpiriva, and has received mixed verdicts on its validity in Europeancourts. Ireland’s High Court last year denied Teva’s request to revokethe local part of the ‘220 patent, although a UK Court of Appeal hadearlier denied Boehringer permission to appeal against a 2015 rulingthrough which Teva invalidated key claims in the UK part of thepatent. The ‘220 patent has also been found invalid and/or revokedin Germany, the Netherlands, Norway and Spain.

The agreement is Glenmark’s second in Europe to in-license aninhalation product, coming three years after the Indian firm signed adevelopment and licensing agreement with Polish firm Celon Pharmacovering a generic of GlaxoSmithKline’s (GSK’s) Seretide Accuhaler(fluticasone/salmeterol) dry-powder inhaler (DPI) in certain Europeancountries (Generics bulletin, 6 November 2015, page 17).

Glenmark’s respiratory ambitions also extend to the US, wherethe firm recently received from the US Food and Drug Administration(FDA) a target action date of 21 March 2019 for the firm’s Ryaltris(olopatadine/mometasone) nasal spray for seasonal allergic rhinitis,filed through the 505(b)(2) hybrid pathway. Before the end of thisyear, the firm intends to meet with the FDA to discuss Phase III trialsfor its GBR310 Xolair (omalizumab) biosimilar. G

ANALGESICS

Alvogen beats Zohydro patentsAlvogen has convinced a Delaware district judge that two patents

protecting Pernix’ Zohydro ER (hydrocodone) extended-releasetablets until July 2033 are invalid as obvious and for failure to satisfythe written-description requirement. Pernix plans to appeal.

In a 109-page ruling, Judge William Bryson found that althoughAlvogen’s formulation infringed US method-of-treatment patents9,265,760 and 9,339,499, the patents were obvious in light of priorart including the Jain patent publication and labels for the hydrocodone/acetaminophen brands Vicodin and Lortab. The patents also failedthe written-description test because their specifications described onlya single species within the broad genus covered by the claims.

Under a 2016 settlement, Alvogen can launch generic ZohydroER “as early as” 1 October 2019, provided it secures final approvalfrom the US Food and Drug Administration (FDA). Pernix’settlement with Actavis allows generic entry from 1 March 2029. G

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PIPELINE WATCH

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

Vortioxetine reaches the end of NCE termTakeda’s Trintellix (vortioxetine hydrobromide) 5mg, 10mg and

20mg tablets lose their US new chemical entity (NCE) dataexclusivity at the end of September 2018. Trintellix, first approvedin September 2013 as Brintellix for treating acute major depressivedisorder (MDD) in the US, is the first treatment for MDD approvedby the US Food and Drug Administration (FDA). The brand-namechange to Trintellix came into effect in May 2016 to decrease the riskof prescribing and dispensing errors due to name confusion withAstraZeneca’s antiplatelet drug Brilinta (ticagrelor).

In May 2018, the FDA approved a supplemental new drugapplication for Trintellix which resulted in the drug’s prescribinginformation being amended to include data on increased processingspeed in cognitive-impaired adults with acute MDD. According toTakeda, the US labelling will now include “data from the largestreplicated clinical studies on an important aspect of cognitive functionin acute MDD – FOCUS and CONNECT”.

The FDA’s Orange Book also lists a separate exclusivity periodprotecting Trintellix until early May 2021. This appears under theexclusivity code M-227, which relates to the “addition to the clinicalstudies section of the labelling with the sub-section entitled digitsymbol substitution test in major depressive disorder”.

Nine US patents are currently listed against the antidepressant inthe Orange Book, two of which – US patents 7,144,884 and 8,722,684 –are indicated to cover the vortioxetine drug substance. Both the

‘884 and ‘684 patents, which expire on 2 October 2022 and 30 June2031 respectively, are also listed as protecting Trintellix’ drug product,as is US patent 4,476,279 that also expires on 2 October 2022.

Six other Orange Book patents, all of which expire on 15 June2027, have patent-use codes covering “use in the treatment of majordepressive disorder to improve processing speed, an aspect of cognitivefunction” or “method of treating depression or major depressivedisorder”. Of those, four were added to the Orange Book this year.

In its financial year ended 31 March 2018, Takeda reported a47.9% increase in sales of Trintellix to US$435 million. All of Takeda’ssales of the brand during the 12-month period came in the US, wherethe Japanese firm at the end of last year filed vortioxetine as a treatmentfor emergent sexual dysfunction. The firm also has the oral drug inPhase III trials for major depressive disorder in its domestic market, butrecently dropped plans to use the drug for attention deficit hyperactivitydisorder (ADHD) in adults due to an “insufficient efficacy responseobserved in Phase II [trials] to justify continued development”.

According to IQVIA’s Ark Patent Intelligence database, four-year US biologics data exclusivity for Merck & Co’s Keytruda(pembrolizumab) oncology blockbuster ends in early September thisyear (see Figure 1). However, that will be followed by an additionaleight-year exclusivity during which biosimilar applicants can file, butnot receive approval from the FDA.

As Figure 2 shows, two human papillomavirus (HPV) vaccinesare losing their European supplementary protection certificates (SPCs)in September 2018 – GlaxoSmithKline’s (GSK’s) Cervarix in mostEuropean Union (EU) countries, and Merck & Co’s Gardasil inSwitzerland. Gardasil SPCs have paediatric extensions to February2019 in EU countries.

Both the vaccines have similar activity and the difference lies inthe strains of HPV against which they act: Cervarix protects againstHPV types 16 and 18 and is approved for use in girls and women aged10-25 years; whereas Gardasil additionally protects against HPVtypes 6 and 11 and is approved for use in girls and women aged nineto 26 years. Gardasil is also approved for treating genital warts andanal cancer in males aged nine to 26.

GSK reported global Cervarix sales that almost doubled to £68million (US$88 million) in the first half of this year, despite a 20% slideto £12 million in Europe. However, that figure was a mere fraction ofthe US$1.27 billion that Merck generated in the same period fromGardasil/Gardasil 9 following a 27% sales rise, with around 54% ofthe brand’s sales generated in the US. G

Figure 1: Molecules for which data exclusivity expires in certain markets duringSeptember 2018 (Source – Ark Patent Intelligence)

Alogliptin AustraliaAmlodipine/Hydrochlorothiazide/ South KoreaOlmesartan medoxomilAsenapine European Union1

Axitinib TurkeyBilastine European Union1

Canagliflozin AustraliaCatridecacog TurkeyCrizotinib AustraliaDecitabine TurkeyDulaglutide US2

Loxoprofen South KoreaLubiprostone TurkeyNepafenac SwitzerlandPembrolizumab US2

Regadenoson European Union1

Teduglutide TurkeyTrastuzumab emtansine AustraliaVernakalant European Union1

Vortioxetine US1 This will be followed by two years of market exclusivity, during which

a generic cannot be placed on the market2 This will be followed by eight years of biologic application approval

exclusivity, during which a biosimilar will not be approved

Data exclusivity expiries in September

INN Country

Figure 2: Molecules for which supplementary protection certificates (SPCs)expire in certain markets in September 2018 (Source – Ark Patent Intelligence)

Everolimus Switzerland

HPV (Type 16, 18) Austria, Belgium, Denmark, Germany,L1 protein (Cervarix) Greece, Ireland, Italy, Luxembourg,

Portugal, Spain, Sweden, UK

HPV (Type 6, 11, 16, 18) SwitzerlandL1 protein (Gardasil)

SPC expiries in September

INN Country

Gen 7-9-18 Pgs.1-24.indd 18 04/09/2018 16:42

A New ANDA Holder Program Fee Approach Under GDUFA IIFeesThe ANDA Holder Program fee schedule for Fiscal Year 2019 was just published by FDA and fees increased by17% from last year. Fees due to the FDA by October 1, 2018 are as follows:

This is a significant expense for many firms. Those with amodest number of ANDAs will again be paying substantialsums for drug products they don’t currently market or that are identified as Discontinued in the Orange Book. Fora small or medium-tier company this can be a dramatic hurdle to retain the assets they worked so hard to own. And,yes, discontinued ANDAs are still considered approved ANDAs for user fee purposes unless the approval is withdrawn.

In addition, a one-timemarketing status report was required to be submitted to the FDA earlier in 2018, identifyingthe submission as “MARKETING STATUS REPORT / ONE-TIME UPDATE.” While there has been no guidance asto what happens to the ANDAs identified as “not marketed”, one scenario may be they will be either movedto discontinued status or have their approval withdrawn.

PenaltiesWhat is the penalty for not paying the program fee?1) If the fee is not paid within 20 calendar days after the due date, the parent company will be placed on a

publicly available arrears list.2) Any ANDA submitted by the applicant or its affiliateswill not be received.3) All drugs marketed pursuant to any abbreviated new drug application held by such applicant or an affiliate

of such applicant shall be deemed misbranded.

A SolutionFor the second year, ANDA Repository, LLC. offers significant user fee relief and a solution for companies thathave discontinued ANDAs or drug products not currently marketed. Like with a parking lot, car owners needspace for their cars, whether in use or not. Only here, in exchange for the space (and a fee) car owners transferstitle of the car to the parking lot owner. The former car owners can, with appropriate notice, resume ownershipwhen they choose to use the car again. Since the parking lot owner has enough cars, this venture benefits forall the parties involved, and the cars remain safe and secure.

In the example above, the car owner is an ANDA owner, and the parking lot owner is ANDA Repository, LLCwhichcharges ANDA owners an annual fee that is significantly less than the ANDA Holder Fee that the FDA charges smallor medium sized firms.

There is NO need to pay excessive fees or be forced to withdraw your valued assetsdue to short-termmarket conditions, capacity constraints, API supplier issues, etc.!

Alternatively, if your choice is toWITHDRAWyour ANDAs, wemay be interested in purchasing them!

URGENT – FY2019 GDUFA Fees JustAnnounced... Increased by 17%

The FY2019 GDUFA Generic Drug Applicant Program Feeis due October 1st so please contact us soon!

Tier ANDAS Owned FeeSmall 1-5 $186,217Medium 6-19 $744,867Large 20 or more $1,862,167

Phone: +1-570-261-1901 Email: [email protected]

Gen 7-9-18 Pgs.1-24.indd 19 04/09/2018 16:42


PEOPLEAPPOINTMENTS

Mexico’s Genommahands Brake top jobJorge Luis Brake is to take on the mantle of chief executive officer

of Genomma Lab Internacional, in line with the Mexican OTCmedicines and personal care specialist’s ongoing long-term strategicand succession planning. Taking the role from 10 September,Brake, most recently senior vice-president at Laureate Education,replaces Maximo Juda, who will remain “active at Genomma in anadvisory role to ensure a smooth transition”.

Welcoming Brake to the company, Genomma said that he wasjoining with “more than 25 years of related industry experience withProcter & Gamble (P&G)”, including as chief executive officer ofP&G’s Latin America division. It also encompassed leadership rolesin sales, marketing, customer service and general management inMexico, Peru, Brazil, the US, Colombia and Central America.

Juda is to step down after three years as Genomma’s head, havingpreviously served as the company’s chief operating officer and takenthe chief executive role from Genomma’s chairman Rodrigo Herrerain 2015 (Generics bulletin, 7 August 2015, page 34).

Brake’s appointment came as Genomma announced that MarcoSparvieri, currently executive vice-president of sales, had expandedhis responsibilities to become executive vice-president of operations.Furthermore, Santiago Velez, who is currently vice-president ofmanufacturing, will also become executive vice-president ofmanufacturing and R&D. G

ALLERGAN director Paul Bisaro is ending his 11-year associationwith the firm after announcing his retirement from the board,“as part of the company’s ongoing board-refreshment process”.Bisaro joined the board of the legacy Watson Laboratories companyin 2007 when he was appointed chief executive officer, staying onas a director in the interim as the company evolved into Allerganthrough mergers and acquisitions. He continues to serve as executivechairman of Amneal Pharmaceuticals.

FORMYCON – the German biosimilars developer – is appointingThomas Siklosi to its advisory board. Describing Siklosi as a“renowned biotech manager and expert in the development andproduction of biologics and biosimilars”, Formycon said he had“been involved with biotechnology right from the start”. His previousexperience includes a six-year stint as chief operating officer withRentschler Biopharma that ended in February this year.

TRIS PHARMA has appointed the quality head for Lupin’sSomerset, New Jersey manufacturing site, Jeffrey Palmer, as itsvice-president and head of quality and compliance. In a more than20-year career, Palmer has also previously worked with Merck &Co in a number of quality roles.

MEDICINES AUSTRALIA – the country’s originator industrybody – has promoted its deputy chair, Anna Lavelle, to the positionof chair. Taking over the role from the outgoing Wes Cook, Lavellewas Medicines Australia’s first independent director upon herappointment in January last year. She also chairs the body’srecently-established independent advisory council. G

IN BRIEF

Gen 7-9-18 Pgs.1-24.indd 20 04/09/2018 16:42

gen 7-9-18 pgs.1-24 · 2018. 10. 29. · “tevaannounced multiple plant closures anda15% reduction...

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