Gen 18/11/05 Pg. 1

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4 October 2013

Mylan must sell 11 to buy Strides’ Agila 3Hikma teams up for 3presence in EthiopiaNavamedic proclaims Benelux ‘bridgehead’ 4Actavis agrees in US to divest to Amneal 5Grünenthal lines up Chilean acquisition 5Aarti Drugs acts on FDA warning letter 6

MARKET NEWS 7

MSF slams US over Indian ‘retaliation’ 7CGPA attacks Lilly on promise doctrine 8IGPA urges Australia to use 9identical INNsGPhA petitions for shared biologic INNs 10EGA urges focus on 11African collaborationSwiss should follow EU biosimilar model 11

PRODUCT NEWS 12

Sandoz gains licence for 12Orion combinationJapan may be model for biosimilar INNs 13Stada Spain adds toAlzheimer’s portfolio 16Sandoz and Reddy’s battle 17on azacitidineReddy’s Lunesta win is reversed on appeal18US court bars Hanmi on 19esomeprazole rival

FEATURES 24

Prosonix sounds out options 24for its respiratory platformUK-based respiratory specialist Prosonix istalking to prospective partners aboutmarketing generics and supergenerics madeusing its ultrasonic, particle-engineeringtechnologies. Aidan Fry reports.

REGULARS

Events – Our regular listing 20

Paragraph IVWatch – Rayos 21

PriceWatch UK – Our in-depth 23look at pricing trends in the UK

People – FDA’s Webber gets 27new role at Perrigo

COMPANY NEWS 3

Servier has made an offer worth HUF107 billion (US$481 million) to take full controlof its Hungarian affiliate Egis. The French group is offering HUF28,000 per share for

approximately 3.82 million outstanding shares that it does not currently own, valuingEgis at HuF218 billion. The French group has since 1995 held a majority 50.91% stakein Egis through a wholly-owned subsidiary.

“Egis is the only listed company within Servier, but has no need to use the equity capitalmarket for financing, so we believe being listed on the Budapest Stock Exchange makes littlefinancial sense for Egis,” the French group’s president and founder Jacques Servier insisted.

“Servier does not intend to make any significant changes to the strategy or operations ofEgis,” the French group stated, adding that there were “very limited incremental synergiesavailable”. That strategy, it noted, included looking to enter new markets through acquisitionsfunded by its own profits; expanding its portfolio of both finished-dose generics and activepharmaceutical ingredients (APIs); and investing in distribution and marketing for biosimilarssuch as its Flammegis (infliximab) monoclonal antibody that the Hungarian firm is rolling outin central and eastern Europe (CEE) through a deal with South Korea’s Celltrion (Genericsbulletin, 12 July 2013, page 12). Egis’ current management team will remain in place.

Generics accounted for around a quarter of Servier’s group turnover of C3.93 billion (US$5.31billion) in its most recent financial year. The generics total of approximately C980 million includedabout C580 million from France’s Biogaran, C390 million from activities in CEE countries andthe Commonwealth of Independent States (CIS), and C15 million through Brazil’s Pharlab.Egis is set to achieve a turnover of around USS$600 million in its financial year to September.

Noting that its final offer for the outstanding 49.09% of Egis’ shares offered a 33% premiumover the firm’s closing price on 23 September – Egis’ last day of trading preceding theannouncement – Servier added that this extended to a premium of 38% when taken over Egis’average trading price for the six months ended the same date. Hungary’s Financial SupervisoryAuthority is currently examining the deal. Once cleared, the offer will be open for 30 days. G

Hungary’s Egis will befully owned by Servier

France has unveiled plans to save C870 million (US$1.18 billion) from the country’s healthcarespending in 2014 by cutting the prices of generics and brands, as well as by more closely

aligning the prices of medicines listed within France’s répertoire of generic equivalents. Savingsof around C165 million will come from “optimising tariffs for generics”, according to budgetproposals published by the government, while “price convergence” within the répertoire willsave C200 million and reducing prices for off-patent products will lead to savings of C245 million.

Restricting growth in France’s healthcare spending to a target of 2.4% in 2014 requiressavings of around C2.4 billion, the budget document states. As well as the measures planned forgenerics and off-patent medicines, the country’s government expects to produce savings of C260million through price cuts for brands and C70 million from reducing prices for medical devices.

“Taking control of healthcare spending should not come at the cost of patient care but througha more efficient use of the resources of the healthcare system,” the document insists. Along withprice cuts for generics, it also recommends improving the transparency of generics pricing –including by declaring rebates offered to pharmacists by manufacturers – and taking steps toencourage the use of biosimilars by providing better information to prescribing doctors. G

For local generics association GEMME’s reaction to the announcement, turn to page 10.

France intends to slash prices

Gen 4/10/13 Pg. 1_Gen 18/11/05 Pg. 1 02/10/2013 19:05 Page 1

Mylan must divest rights to 11 marketed or pipeline genericinjectables as a condition of securing clearance from the US

Federal Trade Commission (FTC) for the firm’s US$1.85 billiontakeover of Strides Arcolab’s Agila division.

According to the FTC, Mylan’s pending purchase of Agila will“lessen current and future competition in each of the 11 genericinjectable product markets”. To remedy this, the competition watchdoghas told the two firms to divest rights to fluorouracil and methotrexateto Intas; amiodarone, etomidate, fomepizole, ganciclovir, meropenemand mycophenolate to JHP; and acetylcysteine and mesna to Sagent(see Figure 1). The FTC has also told Mylan to hand all rights tolabetalol to its Indian contract-manufacturing partner, Gland Pharma.

According to the FTC, Mylan currently holds a 60% market sharefor the antiarrhythmic agent amiodarone, with the other 40% splitbetween Fresenius Kabi and Hikma. “Agila has an approved abbreviatednew drug application (ANDA) and is about to enter this market, asis one other firm,” the Commission observed.

Mylan and Agila – through its distribution deals with Pfizer andSagent – would have a combined market share of 46% for the anaestheticetomidate. And in the “highly concentrated market” for the cancerdrug fluorouracil in which Fresenius, Mylan, Sandoz and Teva wereplayers, several suppliers had “experienced significant manufacturingissues”. Agila held an approved ANDA for fluorouracil, the FDA noted.

Five firms – Agila, Akorn, Apotex, Hospira and Mylan – couldsupply the antihypertensive labetalol. Other than Agila and Mylan,only Baxter and Fresenius Kabi marketed the detoxifying agent mesna.Excluding Mylan and Agila, Fresenius, Hospira and Teva marketedmethotrexate for treating cancers and autoimmune disorders.

The FTC said Mylan and Agila were two of only a limited numberof firms developing acetylcysteine to treat acetaminophen overdoses.The two firms were also working towards joining Fresenius in offeringa generic rival to Roche’s Cytovene (ganciclovir) antiviral agent.

Mylan – like Sandoz and X-Gen – currently marketed fomepizolefor treating accidental poisoning, while Agila was developing the drug.Mylan and Agila were “the only likely entrants that will source theirmeropenem from alternative manufacturing sites” to current players.

And the two firms were among a limited number of potential rivalsto Roche’s CellCept (mycophenolate mofetil) immunosuppressant. G

COMPANY NEWS

3GENERICS bulletin4 October 2013

MERGERS & ACQUISITIONS

Mylan must sell 11to buy Strides’ Agila

Active ingredient Vendor Purchaser

Fluorouracil Mylan IntasMethotrexate Mylan Intas

Etomidate Mylan JHPGanciclovir Mylan JHPMeropenem Mylan JHPMycophenolate Mylan JHPAmiodarone Agila JHPFomepizole Agila JHP

Acetylcysteine Agila SagentMesna Agila Sagent

Labetalol Mylan Gland

Figure 1: List of 11 drugs, and their purchasers, that Mylan and/or Agila mustdivest in the US to complete their US$1.85 billion transaction (Source – FTC)

Hikma has formed a joint venture with Saudi Arabia’s MidrocPharmaceuticals to establish a presence in the Ethiopian pharma

market. The two firms will each provide up to US$22.3 million incash for the 50/50 venture, which the Jordanian company said wouldbe called ‘HikmaCure’.

Noting that imports made up three-quarters of Ethiopia’s US$500million pharmaceuticals market, Hikma said the funds would be usedto build and equip a manufacturing and distribution centre in Ethiopiathat was expected to start commercial production in 2017.

Meanwhile, the partners will collaborate on registering, marketingand distributing Hikma’s portfolio in Ethiopia.

Expanding into sub-Saharan Africa“Expanding our presence into sub-Saharan Africa is a key strategic

priority for Hikma, and this is an excellent first step,” stated Hikma’schief executive officer, Said Darwazah. “We will continue to exploreopportunities to build our presence in the sub-Saharan region,” he added.

Ethiopia, Darwazah observed, offered “strong growth potentialin the medium to long term”. An anticipated compound annual growthrate of 15% would take the market value to US$1 billion by 2018, heforecasted, while almost two-thirds of the country’s 94 millioninhabitants were aged under 25 years.

Hikma already has an extensive presence in North Africa, includingin Algeria, Egypt, Libya, Morocco, Sudan and Tunisia. Its Brandedbusiness segment in the Middle East and North Africa (MENA) regionaccounted for US$257 million, or two-fifths, of group turnover totallingUS$638 million in the first half of this year, while the MENA regionalso contributed US$40.1 million to total sales of US$247 millionby the firm’s Injectables segment. G

STRATEGIC ALLIANCES

Hikma teams up forpresence in Ethiopia

Strides Arcolab is anticipating its “first approval of a niche semi-solidproduct” in the US by early next year after the country’s Food

and Drug Administration (FDA) cleared the Indian company’sBeltapharm facility in Milan, Italy.

Manish Gupta, chief executive officer of Strides’ Pharma solid-dose, semi-solids and liquids division, said the FDA’s clearancepaved the way for the firm to enter “the attractive but complex semi-solids market in the US”. “Our first product, which is expected to becommercialised by the first quarter of 2014, has undergone extensiveclinical trials,” he said, adding that it would be “marketed by one ofthe top 10 generics companies in the US market”.

At present, Strides has more than a dozen liquid and semi-solidproducts either in development or pending approval in the US andthe European Union (EU). The Indian firm already sells semi-soliddrugs in the UK.

Strides acquired the Beltapharm plant – which makes semi-soliddelivery forms such as creams and ointments, as well as liquidformulations – around eight years ago (Generics bulletin, 9 September2005, page 11). The site– which has also been certified by EU andAustralian regulators – forms part of the Pharma division that Strideswill retain after it completes the sale of its Agila injectables divisionto Mylan (see opposite). G

BUSINESS STRATEGY/MANUFACTURING

Strides awaits semi-solid nod

Gen 4/10/13 Pgs. 2-6_Layout 1 02/10/2013 19:06 Page 3

Pursuing “downstream integration into formulations and finisheddosages” will be a core strategy for DSM’s anti-infectives business

through to 2015, the Dutch group said during an investors’ day heldin September. The unit – which formed a joint venture with China’sSinochem two years ago – will also look to “upgrade its portfolioattractiveness” while strengthening its core business.

Stefan Doboczky, the member of DSM’s management boardresponsible for the group’s Pharma division, said forming the DSMSinochem joint venture – by selling for C210 million (US$284 million)a 50% stake in the Dutch group’s anti-infectives business to China’sSinochem (Generics bulletin, 16 September 2011, page 3) – hadcreated a “strategically much stronger set-up”. Both commercialmarkets and operational infrastructure in the global antibiotics sectorwere shifting eastwards towards China and India, he observed, socapitalising on Sinochem’s local presence would be crucial.

To improve DSM Sinochem’s cost position through backwardintegration, the business is building a “world-scale” fermentation facilityin China to make 6-APA intermediates for semi-synthetic penicillins.However, Doboczky admitted, ramping up production of the plant hadbeen “slower than planned”.

DSM Sinochem is also pursuing a forward-integration strategy bypushing into finished-dosage forms. In particular, the business has“successfully entered” the statins sector using a process with a“significantly lower carbon footprint”. An API factory that the firm isbuilding in India is scheduled to start producing bulk statins next year.

Doboczky said DSM Sinochem had, since its creation in 2011,grown by 8% to a turnover this year approaching C400 million. However,longer-term sales and profits targets remained “out of reach” as industryover-capacities – such as for 6-APA intermediates – suppressed prices.

The Dutch group has not set short-term sales or profit targets forits Pharma division, as DSM Sinochem is to be deconsolidated fullynext year under accounting rules, and the firm is seeking a partnershipfor its DSM Pharmaceutical Products (DPP) services unit to create“a contract-manufacturing organisation (CMO) industry leader”. G

COMPANY NEWS

4 GENERICS bulletin 4 October 2013

4 October 2013 Issue 199

Editor: Aidan FryDeputy Editor: DavidWallaceBusiness Reporter: Dean RudgeProduction Controller: Debi MinalProduction Editor: Jenna LawrenceDirector of Subscriptions: Val DavisManaging Director: Mike Rice

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BUSINESS STRATEGY

DSM Sinochem aimsto drift downstream

Navamedic claims it has “succeeded in establishing a bridgehead inthe attractive Benelux markets” by launching 10 branded generics

in Belgium during the first half of this year, and introducing anothertwo generics in the Netherlands. The Norwegian firm – which hassupply alliances with partners including South Africa’s Aspen – is nowseeking “a growing presence and improved margins in these markets”.

Having launched its first products in Belgium earlier this year,Navamaedic said the country accounted for 12% – and the Netherlands

9% – of group turnover in the first half of 2013, which advanced bytwo-thirds to NOK72.1 million (US$ 12.0 million).

“Strong sales” in Belgium, as well as “growing volumes” in theNetherlands, helped to double first-half turnover by Navamedic’s Pharmaproduct segment to NOK54.0 million. However, the firm acknowledged,the segment’s earnings before interest, tax, depreciation and amortisation(EBITDA) margin remained “fairly slim” at 2.5% (see Figure 1).

The firm’s Medical Nutrition segment raised its turnover by a thirdto NOK12.4 million. But the loss-making Consumer Care segment’ssales fell by almost a quarter to NOK5.7 million on supply shortages.

Navamedic – which recently saw its chief executive officer, OlofMilveden, leave (Generics bulletin, 12 July 2013, page 2) – said NOK2.6million from a divestment swelled its EBITDA to NOK4.3 million. G

BUSINESS STRATEGY/FIRST-HALF RESULTS

Navamedic proclaimsBenelux ‘bridgehead’

Product First-half sales Change EBITDAsegment (NOK millions) (%) margin (%)

Pharma 54.0 +102 2.5Medical Nutrition 12.4 +35 5.9Consumer Care 5.7 -23 –*

Navamedic 72.1 +67 6.0**

* EBITDA loss of NOK0.4 million ** includes exceptional income of NOK2.6 million

Figure 1: Breakdon by product segment of sales and earnings before interest,tax, depreciation and amortisation (EBITDA) margin by Navamedic in the firsthalf of 2013 (Source – Navamedic)


Grünenthal has signed a deal with two major shareholders to acquirea stake in Chilean generics, brands and OTC player Laboratorios

Andrómaco. The German group said it was “preparing a potentialtakeover” of the Chilean firm later this year.

Following a due-diligence period running until November,Grünenthal plans to launch a public tender offer for all outstandingshares in the Chilean firm, which last year achieved earnings beforeinterest, tax, depreciation and amortisation (EBITDA) of US$36 millionon a turnover of around US$200 million. The firm grew its turnover lastyear by just over a tenth following its acquisition of Colombia’s Labinco.

One of the two major shareholders, vice-chairman Sergio Weinstein,intends to retain up to a 17% minority stake in the company. The othervendor is Moneda Asset Management.

Noting that Andrómaco was one of Chile’s top-five pharmaceuticalcompanies, Grünenthal said it planned to pay CLP330 (US$0.65) pershare for the Chilean firm. Andrómaco noted that this was “around70% above its current market value”.

Highlighting the “strategic fit in terms of regional presence andtherapeutic areas”, Grünenthal’s Latin American head, Oscar Ferenczi,said the combined entity would be “a strong regional licensing partner”.

Among Andrómaco’s leading generic molecules are alprazolam,ambroxol, hydrocortisone, losartan and naproxen. The firm offers awide range of branded prescription and hospital drugs – such asCiproxino (ciprofloxacin), Glifortex (metformin), Traviata (paroxetine) –as well as a roster of OTC remedies.

Last year, Latin America accounted for a fifth, or C194 million(US$262 million), of the German family-owned group’s global turnoverof C973 million. Grünenthal has been active in the region since 1968and already has affiliates in Brazil, Chile, Colombia and Ecuador, aswell as in Mexico, Panama, Peru and Venezuela. G

COMPANY NEWS



Grünenthal lines upChilean acquisition

Daiichi-Sankyo says it is “fully committed” to supporting theefforts of its Ranbaxy subsidiary to strengthen the Indian firm’s

“procedures and policies to ensure data integrity and comply withcurrent good manufacturing practice (cGMP)”.

The Japanese parent group was responding to an announcementby the US Food and Drug Administration (FDA) that it was subjectingRanbaxy’s facility in Mohali, India, to an import alert and to certainterms of the consent decree that the agency had agreed with the Indianfirm in early 2012 over two other Indian plants in Dewas and PaontaSahib (Generics bulletin, 20 September 2013, page 3).

“We will cooperate fully with the US authorities,” Daiichi stated. G

MANUFACTURING

Daiichi will support Ranbaxy

TIANYIN PHARMACEUTICAL blamed “generic pricing pressure”and a lengthy ramp-up of production at its Jiangchuan macrolidesfacility for group turnover falling by 3.0% to US$67.5 million in theChinese firm’s financial year ended 30 June 2013. Ginkgo Mihuanoral liquid accounted for 39% of group sales, mycophenolate mofetilcapsules a tenth, and azithromycin orodispersible tablets 7%. G

IN BRIEF

Actavis has agreed to sell rights to four generic drugs – threeoral contraceptives and an osteoporosis treatment – to Amneal

Pharmaceuticals as a condition of securing US Federal TradeCommission (FTC) clearance for the US$8.5 billion takeover of WarnerChilcott that is has just completed.

A proposed FTC consent order – which is open for publiccomment until 28 October – requires Actavis to sell to Amneal its rightsand assets relating to generic versions of Warner Chilcott’s Femcon Fe,Loestrin 24 Fe and Lo Loestrin Fe oral contraceptive brands, all of whichare based on combinations of norethindrone and ethinylestradiol.

According to the FTC, Actavis’ Zenchent Fe alternative toFemcon Fe currently holds a 70.2% share of the generic market for theoral contraceptive, while Lupin has a 29.7% share with its authorisedgeneric supplied by Warner Chilcott. Teva’s sales of the drug are“de minimis”, the watchdog adds.

There are no generic versions of Loestrin 24 Fe and LoLoestrin Fe currently marketed in the US. However, Actavis holds anapproved abbreviated new drug application (ANDA) for a rival toLoestrin 24 Fe and “is likely to be the first generic competitor” as itcan launch in January next year under the terms of a patent-litigationsettlement (see Figure 1).

Actavis, the FTC adds, could also qualify for 180-day exclusivityfor the alternative to Lo Loestrin Fe that is currently pending ANDAapproval from the US Food and Drug Administration (FDA) and isthe subject of patent litigation involving both Actavis and Lupin.

The FTC notes that Warner Chilcott’s Atelvia (risedronate)delayed-release tablets do not currently face generic competition.“Actavis is one of a limited number of suppliers capable of enteringthe market for generic Atelvia in the near future,” the watchdog says,“and may be the first and only generic competitor to the Warner Chilcottbranded product for a period of 180 days.” Actavis’ANDA is awaitingapproval and is the subject of patent litigation involving Actavis,Ranbaxy and Teva.

Under the terms of the consent order, Actavis has agreed to supplygeneric versions of Femcon Fe and Loestrin 24 Fe to Amneal fortwo years, after which time Amneal can choose to extend theagreement for a further two years.

Actavis will also have to relinquish its claim to 180-day exclusivityfor the generic versions of Atelvia and Lo Loestrin Fe “to preservethe incentives of the companies currently leading the patent litigationsagainst Warner Chilcott related to those products”.

“With 65 other generic products already on the market,” commentsthe competition authority, “the FTC believes Amneal has the expertiseto replicate the competition for the four drugs that otherwise wouldhave been lost through the proposed acquisition.” G


Actavis agrees in USto divest to Amneal

Brand Regulatory status Legal status

Femcon Fe ANDA approved Marketed

Loestrin 24 Fe ANDA approved Settlement permits genericlaunch in January 2014

Lo Loestrin Fe Pending ANDA Patent litigation ongoing

Atelvia Pending ANDA Patent litigation ongoing

Figure 1: Warner Chilcott brands for which Actavis must divest US genericsrights to Amneal, along with the regulatory and legal statuses of Actavis’generics (Source – Actavis/FTC)


COMPANY NEWS


Aarti Drugs says it has hired a US-based consultant to respond toa warning letter the Indian company has received after the US Food

and Drug Administration (FDA) inspected its bulk-drugs facilitieslocated in Tarapur, India.

Among the deviations from current good manufacturing practice(cGMP) listed in the warning letter was recording manufacturing stepsin batch records before they had occurred. Practices such as recordingfinal packed quantities before batches had been weighed, the FDA said,raised “concerns regarding the reliability and accuracy of the datagenerated at your firm, including any other inappropriate data-relatedpractices permitted by your firm when an inspection is not in progress”.

Furthermore, Aarti had failed to investigate the impact on productquality of more than 130 power outages that occurred during 2012. TheFDA also took issue with the firm’s laboratory-control records andwith its audit trails.

“It is apparent that you have not implemented a robust qualitysystem at your firm,” concluded the FDA, which advised Aarti to“undertake a comprehensive evaluation of global manufacturingoperations to ensure compliance with cGMP regulations”.

Acknowledging that some of its initial responses to the inspection“need to be further corrected”, the Indian firm said it was working onenhancing its quality systems. “Aarti Drugs continues to cooperate withthe FDA to resolve the issues at the earliest [opportunity],” it added. G

MANUFACTURING

Aarti Drugs acts onFDA warning letter

GOOGLE has founded Calico, “a new company that will focus onhealth and well-being, in particular the challenge of ageing andassociated diseases”. “With some longer-term, moonshot thinkingaround healthcare and biotechnology, I believe we can improvemillions of lives,” commented Google’s chief executive officer,Larry Page. Art Levinson, who is chairman of both Apple andRoche’s Genentech, will be Calico’s chief executive officer and afounding investor in the company.

STRIDES ARCOLAB failed to ensure that gloves used for asepticfilling were sterile, according to a warning letter sent by the USFood and Drug Administration (FDA) to highlight deficiencies at thefirm’s injectables facility in Bangalore, India (Generics bulletin,20 September 2013, page 5). The Bangalore site forms part of theAgila division that the Indian firm is selling to Mylan (see page 3).Other deficiencies listed in the letter include inadequate media-fillstudies, inadequate systems for monitoring environmental conditions,failures fully to investigate batch failures and “the presence of mouldspores in the cold room”.

SANOFI has started building a production plant for dry and liquidproducts in Sidi Abdellah, Algeria. The French group said the66,000 sq m site would produce 100 million units per year – equivalentto four-fifths of the volume that the group distributed in Algeria – andwould also house a distribution centre. Noting that it already hadAlgerian manufacturing plants in Ain Benian and Oued S’mar, Sanofisaid it would spend three years and almost C70 million (US$95million) on constructing the Sidi Abdellah plant, which would beits largest industrial site in Africa.

OLAINFARM said boosting its sales in Russia by almost a fifth toLVL13.3 million (US$25.6 million) helped to increase its overallturnover by 6% to LVL32.5 million in the first eight months of2013. The Latvian firm improved domestic sales by 30%, whileturnover in Belarus grew by three-fifths. Russia, in contributing41% of sales, remained OlainFarm’s biggest market, while OlainFarm’sdomestic sales made up a further quarter, or LVL7.8 million.OlainFarm’s Belarusian sales contributed 8% of turnover, the sameamount as Ukraine, where sales dropped by three-fifths.

GLENMARK says it has received “a small research-fee payment”from its partner Forest as the two firms collaborate on developingnovel mPGES-1 inhibitors to treat chronic inflammatory conditions.Forest – which will be able to obtain marketing rights once pre-clinical work is completed – made a US$6 million upfront paymentunder the terms of the alliance.

FDA – the US Food and Drug Administration – has secured a consentdecree against hospital-products distributor Shamrock Medical.The agency said the Ohio-based firm had, despite warnings, repeatedlydistributed incorrectly-labelled, non-sterile drugs. Shamrock toldthe FDA it was no longer repackaging or distributing any drugs.

DIAPHARM – the German pharma services group – will open anoffice in Shanghai, China, next year. Noting that China providedthe bulk drugs for many European medicines, the German groupsaid Chinese producers were now looking to expand westwards.

CAPSUGEL says it has expanded and upgraded its finished-dosefacilities in Ploermel, France and Livingston, UK, as well as inGreenwood, US. The US-based manufacturer said the investmentswould help it meet growing demand for soft-gel and liquid-filledhard capsules. G

IN BRIEF

Bioton says it is taking “immediate action” to find a partner orpartners for its biosimilar insulin candidates in markets including

the European Union (EU) and the US.A previous insulins deal that the Polish firm had struck with Actavis

was terminated earlier this year after Actavis was acquired by Watson(Generics bulletin, 1 February 2013, page 15).

Noting that it was pursuing regulatory approval for its insulins inthe EU, US and Japan, the firm said it would seek marketing deals with“international pharmaceutical concerns, following the model assumedin other long-term contracts concluded by Bioton, such as with BayerHealthCare and GlaxoSmithKline”. Bayer markets Bioton’s insulinsin China, while a similar deal with GlaxoSmithKline covers Russia.

Partner for sustained-release somatropinThe Polish group – which does not anticipate any income from

insulin sales in the EU, US or Japan before 2017 – will work with “aninternational pharmaceutical company” to market the sustained-releasesomatropin for which its BioPartners unit recently secured EuropeanCommission approval (Generics bulletin, 20 September 2013, page 21).

Bioton’s group turnover fell by 28% to PLZ166 million (US$53.1million) as reported in the first half of this year. But excluding PLZ94.7million in the prior year linked to the terminated agreement withActavis, turnover advanced by 23%, due in part to higher sales ofgrowth hormones through the group’s SciGen subsidiary.

Growth hormones accounted for 11% of group sales, insulins41% and antibiotics and other generics 16%. Other products madeup the remainder. Domestic sales contributed a third of the Polishgroup’s turnover, Italy 11%, and Australia and Russia each 9%. G

BUSINESS STRATEGY/FIRST-HALF RESULTS

Bioton seeks insulin partner


Issues arising from comments to date on three draft overarchingbiosimilars guidelines will be discussed during a one-day workshop

hosted by the European Medicines Agency (EMA) on 31 October.Among the topics to be debated will be: the choice of reference

product and three-way comparability exercises; the concept of ‘qualitytarget product profile’ and the use of different expression systems tothe originator; stepwise approaches to non-clinical programmes; andbiosimilar-specific clinical models and endpoints.

On each issue, the “biosimilars industry” is scheduled to makea 10-minute presentation, as is the “innovator industry”. Thesepresentations will then be followed by panel discussions of just overan hour that will be chaired by EMA staff.

According to the agency, invitations to participate in the workshop– which will be streamed live online and recorded – will be sent to“stakeholders who provided comments on the draft guidelines andspecifically-invited interested parties”. The workshop will coincide withthe final day for submitting written comments on the overarching draftguideline on biosimilars containing biotechnology-derived proteinsas an active substance (Generics bulletin, 17 May 2013, page 14).

Having already invited public comments on an overarchingbiosimilar quality guideline last year, the EMA has set a deadline of30 November 2013 for comments on an overarching guideline on non-clinical and clinical issues (Generics bulletin, 28 June 2013, page 17). G

MARKET NEWS


REGULATORY AFFAIRS

EMA sets date forbiosimilars workshop

India is facing “an onslaught of political pressure from the USgovernment and industry in retaliation for the country’s entirely

legal actions to limit abusive patenting practices and increase accessto affordable generic medicines”, according to doctors’ humanitariangroup Médecins Sans Frontières (MSF).

According to MSF, that pressure was likely to increase as USPresident Barack Obama met with Indian Prime Minister ManmohanSingh for talks, including negotiations on a bilateral investment treaty.

Indian court decisions to deny Novartis a patent for a salt formof imatinib and to uphold a compulsory licence granted to local firmNatco for a rival to Bayer’s Nexavar (sorafenib) were “compliant withall World Trade Organization (WTO) rules on trade”, MSF insisted.

“Nevertheless,” the doctors’ group continued, “some USpharmaceutical firms – led by Pfizer – are crying foul, and are wronglyalleging that India’s patent system is not consistent with the WTO’sagreement on trade-related aspects of intellectual property rights (TRIPS).”The Indian Pharmaceutical Alliance (IPA) recently refuted Pfizer’sclaims in a letter to the originator aimed at “clarifying perspectives” overIndia’s patent regime (Generics bulletin, 6 September 2013, page 16).

In particular, MSF is concerned that the US government will pushfor provisions in the trade deal that would allow pharma companiesto sue the Indian government through an ‘Investor-State DisputeSettlement’ arrangement. G

INTELLECTUAL PROPERTY

MSF slams US overIndian ‘retaliation’


Criticism of Australian drug prices by local lobbying group theConsumer Health Forum (CHF) “does not recognise the significant

differences in the way medicines are supplied in Australia” comparedto other countries such as New Zealand and the UK, according toAustralia’s Generic Medicines industry Association (GMiA).

In a statement issued by CHF, the group claimed that “every minuteof every day, Australia spends A$2,000 (US$1,880) more than weneed to on prescription medicines”. This was because “Australia’smedicine pricing policies have failed to reflect the plunge in worldpharmaceutical costs in recent years”, the CHF stated. The country’s‘price disclosure’ system – which brings prices listed on Australia’sPharmaceutical Benefits Scheme (PBS) in line with actual marketprices paid by pharmacists – “has been too slow to deliver and needsto be sped up”, the CHF insisted.

But the GMiA observed that a “fundamental difference” was thatAustralian patients were free to choose original brands over generics,adding that one out of every four off-patent medicines dispensed onthe PBS was the original brand.

Australian prices ‘the most competitive’“Australian manufacturers of generic medicines already supply

medicines at the most competitive worldwide prices,” the GMiAinsisted. It pointed out that generic antibiotics such as amoxycillin andcephalexin cost the PBS as little as A$0.85 and A$1.04 per packrespectively, which was “well below the cost of a cup of coffee”.

“The CHF appears to be calling for the slashing of genericmedicines prices without consideration of policies that exist in the UKand New Zealand that deliver strong uptake and use of genericmedicines,” the GMiA observed. However, the association noted,“Australian industry does not have the benefit of policies that achievehigh levels of utilisation of generic medicines”.

Furthermore, the GMiA said, while manufacturers with sole-supplydeals in New Zealand benefitted from economies of scale, this system“significantly increases the risk of out-of-stock situations – a situationthat is currently unusual in Australia”.

And in the UK, doctors tended to prescribe by internationalnon-proprietary name (INN), while in Australia “medicines are regularlyreferred to by their brand name, making substitution from the originalbrand to the generic medicine more difficult”. G

MARKET NEWS


PRICING & REIMBURSEMENT

GMiA rebuts attackon Australian pricing

Comments made by Eli Lilly’s chief executive officer, John Lechleiter,criticising Canada’s intellectual-property (IP) regime “reflect the

disappointment of an unsuccessful litigant” and are “part of a self-interested advocacy campaign by brand-name pharmaceutical companiesthat seeks to weaken the Canadian patent system”, according to theCanadian Generic Pharmaceutical Association (CGPA).

In a Forbes article entitled, ‘How lax patent rules in Canada aresuffocating life-saving innovation’, Lechleiter claims that Canadian courtshave “arbitrarily created and retroactively applied a standard for whatis ‘useful’ under Canadian law”. By applying this “promise of the patentdoctrine”, Lechleiter insists, “the courts have set a standard found inno other developed country, and one that is more or less impossiblefor an innovative pharmaceutical company to consistently meet”.

Canada’s approach has led the country’s courts to invalidatelocal patents protecting Lilly’s Strattera (atomoxetine) and Zyprexa(olanzapine) brands (Generics bulletin, 11 January 2013, page 14).

However, the CGPA insisted that, “like everywhere else in theworld, Canadian patents must meet three basic criteria: inventionsmust be new, useful and inventive”. The “utility doctrine” exists “toprevent the grant of speculative patents that over-promise and under-deliver”, the association stated, adding that such patents were “harmfulto society and stagnating to innovation”. Moreover, the CGPA observed,“every sophisticated patent system has a way to prevent innovationfrom being stymied by early speculative patenting”.

Furthermore, the CGPA said Lilly had adopted an “extremeposition” by seeking at least C$500 million (US$485 million) in damagesfrom the Canadian government over the Strattera and Zyprexa decisionsthrough arbitration under the North American Free Trade Agreement(NAFTA) “if Canada does not get in line with Eli Lilly’s corporateobjectives” (Generics bulletin, 6 September 2013, page 23). G

PATENT LITIGATION

CGPA attacks Lillyon promise doctrine

Convincing the European Commission to allow generics andbiosimilars manufacturers to manufacture products within European

Union (EU) supplementary protection certificate (SPC) periods forexport to countries such as Russia and Ukraine was amongst the topicsdiscussed by European Generic medicines Association (EGA) PresidentGudbjorg Edda Eggertsdottir during a recent meeting with VytenisAndriukaitis, health minister of Lithuania. The country currentlyholds the EU Presidency until the end of 2013.

According to the EGA, such a ‘manufacturing Bolar’ provisionwould not only create jobs in Lithuania and other EU memberstates, it would also improve access to high-quality medicines in theCommonwealth of Independent States (CIS).

Eggertsdottir also discussed with Andriukaitis pricing mechanismsand reimbursement systems – as well as incentives for pharmacists andpatients – that could improve generic uptake in Lithuania.

Furthermore, Eggertsdottir asked the minister to support theCommission’s proposals in its revision to the Transparency Directive.This would shorten pricing and reimbursement review times for generics,as well as ban explicitly patent linkage and improve coordinationbetween pricing and reimbursement authorities (Generics bulletin,15 February 2013, page 12). G

INTELLECTUAL PROPERTY/MANUFACTURING

EGA engages with Lithuania


Biosimilars should be registered with the same international non-proprietary names (INNs) as their equivalent originator brands

in Australia, the International Generic Pharmaceutical Alliance (IGPA)has urged. The country’s Therapeutic Goods Administration (TGA)had recently published draft guidance suggesting that biosimilar namesshould comprise both the originator INN and an additional uniqueidentifier code to distinguish the biosimilar from its brand equivalent(Generics bulletin, 6 September 2013, page 19).

But the IGPA – which unites the generics industry associationsof Canada, Europe, Japan, Jordan, South Africa and the US – said ithad “serious concerns about the naming recommendations”. Insistingthat “science should be the grounding basis for nomenclature”, theIGPA warned that originator firms had initiated a “concerted globaleffort to thwart competition” by promoting the need for uniquebiosimilar INNs, “in spite of a complete lack of objective data tosupport the need for unique names”.

“IGPA is very concerned that the TGA has made this decision,which is inconsistent with other global regulatory bodies such as theEuropean Medicines Agency (EMA), who has the most significantglobal biosimilar experience,” the international association stated.

“There have been no reported cases of misidentification or failureof pharmacovigilance systems due to the INN for the biosimilar beingthe same as for the reference product,” the IGPA observed, adding thatthe TGA had already approved three filgrastim biosimilars with identicalINNs. “There is no good reason to change policy and no good reasonto diverge from the current position,” the alliance insisted.

“Instead,” the IGPA suggested, “to avoid confusion and mitigatemedication error, biosimilar therapeutics could be identified by a uniqueproprietary name – a brand or trade name.” This, the alliancebelieves, would “provide the differentiation desired without creatingconfusion for healthcare professionals”. “Prescribing biologics by brandor trade name is a longstanding practice in Europe and has not changedwith the market entry of biosimilar medicines,” the IGPA noted.

“The IGPA requests that any final guidance by the TGA on theevaluation of biosimilars include the recommendation to utilise the sameINN as the originator to reflect that the similar biological product hasbeen determined to be highly similar,” the association said in a letter tothe Australian agency. Ultimately, the IGPA warned, a lack of globalconsistency in naming biosimilars would lead to “a loss of scientificbasis for naming, confusion and uncertainty for practitioners and patients,and inappropriately-delayed access to affordable biologicals”. G

MARKET NEWS


BIOSIMILARS

IGPA urges Australiato use identical INNs

SOUTH AFRICA’s Department of Health is inviting comments fromindustry stakeholders on how it should calculate the annual adjustmentto the country’s fixed ex-factory price, the single exit price (SEP).Factors that would be taken into account when adjusting the SEPincluded foreign exchange rates, international pricing information,and “the need to ensure the availability, affordability and quality ofmedicines” in South Africa, the Department of Health noted.Comments should be submitted by 20 December 2013.

FRANCE’s generics industry association, GEMME, has welcomedthe approval of infliximab biosimilars Inflectra and Remsima by theEuropean Commission (Generics bulletin, 20 September 2013, page17). European Union (EU) member states “should now ensure theapplication of appropriate pricing and reimbursement conditions forthese products”, GEMME said, urging French authorities to promotethe use of biosimilars as part of efforts to reduce healthcare costs.

FDA – the US Food and Drug Administration – has formed a‘programme alignment group’ aimed at “identifying and developingplans to modify the FDA’s programmes and functions”. This will helpthe agency address challenges posed by new legislation, globalisationof the medical supply chain and “the increasing breadth, depth andcomplexity of the products it regulates”. Comprising “senior agencyleaders”, the group includes Janet Woodcock, director of the FDA’sCenter for Drug Evaluation and Research (CDER).

TURKEY’s Pharmaceutical Manufacturers Association (IEIS)has welcomed Daiichi-Sankyo as a member. The firm had beenoperating in Turkey since 2008, IEIS observed.

GMIA – Australia’s Generic Medicines industry Association – haspublished a revised draft of its code of practice for publicconsultation. The new edition incorporated recommendations fromAustralia’s parliamentary working group on the promotion oftherapeutic products, the GMiA noted. Feedback on the documenthas been solicited until 31 October 2013.

EUROPE’s unitary patent court (UPC) preparatory committee haslaunched a “call for expression of interest” from judges who wishto nominate themselves to join the future single European patentcourt. The closing date is 15 November 2013.

GPhA – the US Generic Pharmaceutical Association – has welcomed adecision by the US House of Representatives to pass the Drug Qualityand Security Act. The legislation “establishes a uniform nationalstandard for electronic prescription medicine tracking that will furthersafeguard our nation’s prescription drug supply”, the GPhA said.

SPAIN has passed legislation modifying post-authorisationobligations for medicines manufacturers, as well as transparency andpublicity requirements. The decree incorporates requirements ofrecent European pharmacovigilance directive 2010/84/EC and falsifiedmedicines directive 2011/62/EC.

WHO – the World Health Organization – has introduced fees formanufacturers seeking to prequalify formulations or activepharmaceutical ingredients (APIs) under the WHO’s Prequalificationof Medicines Programme (PQP) from 1 September 2013. Fees willbe between US$3,000 and US$8,000, depending on how many PQPapplications have been submitted by the manufacturer. Meanwhile,fees of US$1,500 or US$3,000 will apply for “major variations of apreviously prequalified medicine”, depending on whether the standardor expedited process is used. G

IN BRIEF

California’s healthcare system could save more than US$27.6 billionover a 10-year period “by having access to safe, cost-effective

biosimilar medicines”, according to a report by Express Scripts citedby the US Generic Pharmaceutical Association (GPhA). The report“bolsters the argument that adding hurdles to the biosimilar pathwaycan only do harm to patients, payers and the general public”, theGPhA insisted, urging California’s governor to veto legislation recentlypassed by the US state’s senate that would place additionalresponsibilities on pharmacists who dispense biosimilars (Genericsbulletin, 6 September 2013, page 15). G

MARKET RESEARCH

GPhA cites biosimilar savings


Plans announced by France’s government to slash generics pricesas part of measures to cut healthcare spending in 2014 are “unfair

and incoherent”, according to local generics industry association,GEMME. The association stated that it “deplores these purely financialmeasures”, warning that “draconian” cuts would put at risk the stabilityof an industry that already enjoyed only slim margins.

By attempting to generate savings of more than C200 million(US$271 million) from price cuts in the generics sector (see front page),GEMME said, the government would create “a completely unsustainablesituation for generics manufacturers”.

Moreover, the projected savings were disproportionate to the sizeof the generics sector in France, GEMME pointed out, observing thatthe figure represented around 8% of the total healthcare savingsanticipated as a result of the proposals, whereas generics onlyaccounted for 2% of the country’s healthcare spending.

“GEMME once again regrets that the French government has notseized the opportunity to take courageous, long-term, structural stepsthat would allow it to reduce the healthcare deficit,” the associationstated. In particular, it claimed, policies encouraging the use of genericscould allow France to achieve annual savings of around C4.4 billionthrough using generics.

Meanwhile, GEMME welcomed the government’s recognitionof biosimilars as a tool for reducing healthcare costs. However, theassociation suggested that information about biosimilars to be providedto prescribing doctors as part of efforts to develop the biosimilarsmarket in France – which GEMME described as an “importantadvance” – should also be communicated to pharmacists and patients.

Furthermore, the association stated, while the French budget plansmentioned the possibility of biosimilar substitution and creating arépertoire of biosimilar equivalents, such measures should beaccompanied by efforts to raise awareness, build trust and improve theunderstanding of biosimilars among healthcare professionals. G

MARKET NEWS


PRICING & REIMBURSEMENT

French associationslams price cut plans

All biosimilars should share their international non-proprietary name(INN) with their reference product, according to a citizen petition

that the US Generic Pharmaceutical Association (GPhA) has filedwith the US Food and Drug Administration (FDA).

“It’s simple,” insisted the GPhA’s president and chief executiveofficer, Ralph Neas. “Biosimilars have no clinically meaningfuldifference from the reference product, so they should have the samename,” he said. “This approach works in Europe, it has worked in theUS for chemical drugs, and it should be the standard worldwide.”

In the petition, the GPhA points out that the agency already usesthe ‘highly similar’ standard to permit original biological drugs to bemarketed under the same INN following manufacturing changes. Theassociation says it is “unaware of pharmacovigilance issues that havearisen as a result of products sharing the same INN”.

Indeed, the GPhA maintains, requiring unique INNs for biosimilarswould “compromise patient safety” by encouraging prescribing errorsfrom confused clinicians, limiting patient access to treatments anddisaggregating biosimilars from pooled pharmacovigilance data.

Moreover, the petition points out, “without new statutory authority,the FDA lacks the specific authority to require separate INNs forbiosimiliars”. As a result, the GPhA states, “existing conventions forbiologics should be expected to prevail”.

Reacting to the association’s petition, Amgen said it was“disappointed that the GPhA has resorted to framing the debate betweenidentical and unique names”. “We believe that this presents a falsechoice,” the originator stated.

“As a biologics and biosimilars manufacturer,” Amgen insisted,“we feel strongly that all biologic medicines need a distinguishablecomponent in their non-proprietary name.” To this end, the brandcompany added, it would be “seeking distinguishable non-proprietarynames” for biosimilars. These, Amgen said, should comprise a commonroot coupled with a “distinguishable component”. G

BIOSIMILARS

GPhA petitions forshared biologic INNs

Italian generics captured almost a fifth of the country’s medicinesmarket by volume in the year ended June 2013, according to IMS

Health data cited by the Italy’s generics industry association,Assogenerici. Unit sales of 326 million packs meant that genericsenjoyed a 17.7% share of the total, representing a rise of 1.2 percentagepoints over the previous period’s figure of 16.5%. Of the availableoff-patent market, the share was just over a quarter, or 26.9%.

Annual generics sales of C1.01 billion (US$1.37 billion) at ex-factory prices over the same period accounted for just under a tenth– 9.28% – of Italy’s medicines market by value, compared to 8.41%in the previous 12 months. By value, Italian generics captured a 17.7%share of the off-patent market, meaning that off-patent brands managedto retain 82.3% of sales.

Meanwhile, Assogenerici has criticised the “excessive bureaucracyand slow payments” from the Italian authorities as “the main obstaclesfacing the Italian generics industry today”. Furthermore, stated theassociation’s president, Enrique Häusermann, Italian genericsmanufacturers had to carry a tax burden that was “among the highestin Europe”, despite the relatively low margins of the generics industry.G

MARKET RESEARCH

Italian share continues to riseBrand companies may be using the US Food and Drug

Administration’s (FDA’s) citizen petition process to attempt to delaygeneric competition, according to a report published by the agency.The FDA said it was concerned over petitions that asked the agencyto take action relating to pending abbreviated new drug applications(ANDAs) or hybrid 505(b)(2) applications but that “do not raise validscientific issues and are intended primarily to delay the approval ofcompeting drug products”.

Furthermore, the FDA suggested, originators were “implementingstrategies to file serial petitions” in an attempt to delay rival approvals.Multiple petitions were received “frequently from the same petitioner,about the same specific drug or class of drugs, sometimes requiringseveral separate responses about different issues regarding the sameproduct”, the FDA noted. “Responding to such serial petitions requiresthe use of substantial FDA resources, on a repeated basis, over aprotracted period of time,” the agency insisted, adding that it was“continuing to monitor whether this trend will continue”.

Between 27 September 2007 and 30 September 2012, the FDA said,just five ANDAs with related petitions had their approvals delayed. G

REGULATORY AFFAIRS

FDA concerned over petitions


Allowing advanced manufacturing of generics in Europe for exportto Africa while brands are still protected by supplementary

protection certificates (SPCs) is among the recommendations putforward by the European Generic medicines Association (EGA) to“enable closer cooperation between the European and Africanpharmaceutical industries”. A Bolar-type early working provisionwould be “a first concrete step” towards “a speeding-up of regulatorycollaboration between governments and industry”, the EGA believes.

At a pharmaceutical ‘business to business forum’ covering theEuropean Union (EU) and Africa, the EGA suggested that closercollaboration between the European and African pharmaceuticalindustries would allow patients in Africa to “benefit from high qualityand cost-competitive treatments produced in Europe”. This would alsolead to the development, “over time”, of “a high quality local productionbase in Africa to serve local markets”, the association suggested,insisting that “there is a real opportunity for industrial cooperation onthis basis in the future” (see also page 8).

The EGA’s newly-appointed director general, Adrian van den Hoven,said the forum was “only the beginning for EU-African health policycooperation which must be based on cooperation with the Europeangeneric and biosimilar medicines industries”. “The EGA looks forwardto expanding this activity to establish closer ties between EU industrialpolicy and partnership with African industries,” he added. G

MARKET NEWS


REGULATORY AFFAIRS

EGA urges focus onAfrican collaboration

Swiss regulators should seek to create “the best general conditionspossible” for biosimilars by following the framework adopted by

the European Union (EU), according to Switzerland’s generics industryassociation, Intergenerika.

Future healthcare savings would increasingly come from biosimilarrivals to branded biotech drugs, Intergenerika said, pointing out thatAbbVie’s Humira (adalimumab) had recently supplanted Pfizer’s Sortis(atorvastatin) – sold as Lipitor in other markets – as Switzerland’shighest-selling drug, following the onset of generic competition to thecholesterol-reducing brand.

It was “absolutely essential to not place regulatory obstacles” inthe path of the developing biosimilars industry, the association insisted,observing that the “specific requirements” of the Swiss authoritieswere delaying the arrival of biosimilar competition in the country. “Noone is developing such products for Switzerland,” Intergenerika stated,noting that this was leading to higher prices for biologics.

Meanwhile, Intergenerika has also attacked studies that havecriticised Switzerland for high generics prices. Comparing Swiss genericsprices with those of other countries was like “comparing apples andpears”, Intergenerika insisted, noting that the small size of the Swissmarket and the country’s specific regulatory requirements – as well asa recent rise in regulatory fees commanded by local agency Swissmedic– all contributed to higher prices in Switzerland. G

REGULATORY AFFAIRS

Swiss should followEU biosimilar model


PRODUCT NEWS


GlaxoSmithKline (GSK) has supplemented a citizen petition filedwith the US Food and Drug Administration (FDA) insisting that

certain in vitro comparison methods are “not currently suitable for usein assessing the bioequivalence of locally-acting inhalation products”.The petition follows draft guidance recently published by the FDAoutlining requirements for generic rivals to GSK’s Advair (fluticasone/salmeterol) brand (Generics bulletin, 20 September 2013, page 1).

According to the draft guidance, rivals to Advair should establishbioequivalence with the originator though in vitro studies of all strengthsof the generic to measure their ‘single actuation content’ and ‘aerodynamicparticle size distribution’. A four-week, three-arm clinical trial wouldalso be required to demonstrate bioequivalence, the document indicates.

GSK’s petition includes extracts from research supporting thefirm’s claims that certain methods of statistical comparison for in vitrostudies are insufficient to establish bioequivalence for generic rivalsto Advair. The petition also refers to research that “points out thelimitations of exhaled nitric oxide as a means for comparing localdelivery of inhaled corticosteroids”.

Comparing particle-size profiles via an ‘impactor sized mass’test is “too broad”, the originator argues, while the ‘modified chi-square’ statistical comparison is “not fully developed”. New studieson exhaled nitric oxide and the modified chi-square test had beenpublished since its original petition was filed in 2009, GSK noted.

GSK said it wished to “respectfully request that the FDA makethe data, literature, studies and other information discussed [in thepetition] available to appropriate agency personnel for use in developingguidance for industry or evaluating applications” for generic versionsof orally-inhaled fluticasone and/or salmeterol.

Earlier this year, Mylan said it was aiming to launch a US rivalto Advair in the second half of 2016 (Generics bulletin, 9 August 2013,page 23). Following meetings with the FDA, the firm plans to starta “pivotal clinical programme” by the end of this year and to submitan abbreviated new drug application (ANDA) in early 2015. Therespiratory brand – sold as Seretide in other markets – had US sales of£1.40 billion (US$2.19 billion) in the first half of 2013 (see page 24).G

RESPIRATORY DRUGS

GSK petitions FDAover Advair guidance

Orion has secured a positive opinion from the European MedicinesAgency (EMA) for a Sandoz-branded generic version of its Stalevo

(levodopa/carbidopa/entacapone) combination tablets for Parkinson’sdisease. The marketing authorisation application was made by theFinnish company under an ‘informed consent’ process, whereby anoriginator permits a third party to reference its data.

The positive opinion given by the EMA’s committee for humanmedicinal products (CHMP) covers seven strengths of LevodopaCarbidopa Entacapone Sandoz film-coated tablets.

Intas’ Accord Healthcare obtained a positive CHMP opinion forits generic version of Merz’Axura (memantine) for treating Alzheimer’sdisease. “Studies have demonstrated the satisfactory quality ofMemantine Accord,” the EMA stated. “A bioequivalence study withthe reference product Axura was not required.”

Following an arbitration procedure, the CHMP has advised thatthe benefits of Aurobindo’s didanosine outweigh its risks, so the gastro-resistant tablets should be granted marketing authorisations in France,Germany, Italy, the Netherlands, Portugal, Romania and Spain, as wellas in the reference member state (RMS) for the decentralised procedure,the UK. France and the Netherlands had questioned whether Aurobindohad shown that the hybrid drug was bioequivalent to Bristol-MyersSquibb’s Videx EC antiviral agent, but the CHMP was satisfied withresults for both fed conditions and an empty stomach. G

PARKINSON’S DISEASE DRUGS

Sandoz gains licencefor Orion combination

Acino says a district court in Düsseldorf, Germany, has “smoothedthe way to a pan-European launch” of its once-a-day rivastigmine

patch for treating Alzheimer’s disease.The court denied Novartis and its partner LTS Lohmann a

preliminary injunction they had sought on the basis of German utilitymodel DE20,2006,021,172. Acino’s partner, Betapharm, launchedrivastigmine patches in Germany on 20 April this year (Genericsbulletin, 3 May 2013, page 18).

According to the Düsseldorf court, an injunction was “not justified”because – unlike patents – utility models were “untested intellectual-property rights” that were granted purely on the basis of documentssubmitted by the holder.

Furthermore, Acino said, Novartis and Lohmann had admittedduring proceedings in a Mannheim district court that they did nothave viable claims that the Swiss firm’s patches infringed theGerman part of European patent EP1,047,409. G

ALZHEIMER’S DISEASE DRUGS

Acino wins on rivastigmine


Japan’s system for distinguishing biosimilar international non-proprietary names (INNs) from those of their branded biologic

counterparts could be a model for a global approach, according to theWorld Health Organization (WHO).

As part of its latest consultation on INNs, the WHO observedthat “in Japanese drug nomenclature, a biosimilar is denoted by ‘BS’plus a name for the manufacturer”. “Such an approach could be adoptedby the INN programme,” the global body suggested.

However, the European Generic medicines Association (EGA)insisted that “the use of a unique ‘BS’ suffix to the INN in Japan forbiosimilars has been an impediment to patient access”.

Meanwhile, in Australia – where regulatory guidance has justbeen published recommending unique identifying codes for biosimilarINNs (Generics bulletin, 6 September 2013, page 19) – the EGA said“differences in market penetration” had been seen when different INNswere used for glycosylated biosimilars compared to when the sameINNs were used for non-glycosolated biosimilars.

“The addition of a further suffix will not improve pharmacovigilanceand may cause confusion,” the EGA warned, adding that the creationof new names or identifiers “constitutes a safety issue”. The associationinsisted that “the current situation should be maintained”, suggestingthat “if a product is a biosimilar then the same INN should be used,but if biosimilarity is not shown then there must be a unique INN”.

But the WHO maintained that “there needs to be some way ofdistinguishing between one similar biological product (SBP) and anotherand between the reference product”, adding that “switching betweenSBPs is not desirable”. Although comparability studies were performedbetween SBPs and reference products, the WHO stated, “studies betweenone SBP and another are not done: two separate SBPs may have beencompared to the same reference but not between themselves”.

While biosimilar INNs were “a regulatory authority’s responsibility”the WHO acknowledged, “it is a clear mandate of the WHO’s INNprogramme to ensure clear identification of pharmaceutical substances,both chemicals and biological”. In particular, the global organisationstated, “what needs to be avoided is for individual regulatory bodiesto assign their own non-unified qualifiers”. G

PRODUCT NEWS


BIOSIMILARS

Japan may be modelfor biosimilar INNs

SUN PHARMACEUTICAL has received approval from the US Foodand Drug Administration (FDA) for its rival to Takeda’s Prevacid(lansoprazole) delayed-release 15mg and 30mg capsules. The brandhad annual US sales of around US$430 million, Sun claimed.

NICHI-IKO has entered into an alliance with Thailand’s BioLabthrough which BioLab will distribute the Japanese firm’s productsin the Thai company’s domestic market.

LUPIN has received US Food and Drug Administration (FDA)approval for the Indian firm’s version of Sanofi’s Ambien CR(zolpidem) extended-release tablets in 6.25mg and 12.5mg strengths.Citing IMS Health data, Lupin said that Ambien CR extended-releasetablets had US sales of around US$366 million in the year endingMarch 2013.

MHRA – the UK’s Medicines and Healthcare Products RegulatoryAgency – has instigated a recall of two batches of Morningside’sNatzon (buprenorphine) 0.4mg sublingual tablets. “Due to an errorat the carton printers,” the MHRA said, “a small number of packs maycontain buprenorphine 8mg sublingual tablets in Natzon 0.4mg cartons.”

MYLAN has been sued by Forest Laboratories in the US after filing anabbreviated new drug application (ANDA) containing a paragraph IVcertification against the originator’s Savella (milnacipran) tabletsin 12.5mg, 25mg, 50mg and 100mg strengths. The generics firm saidit expected to be eligible for 180-day exclusivity for its version ofthe fibromyalgia treatment, adding that the brand had US sales ofaround US$123 million in the year ending June 2013, according toIMS Health. Forest said it had also filed suits against Apotex, Hetero,Lupin, Par and Ranbaxy over similar paragraph IV ANDAs.

HOSPIRA and Celltrion’s European infliximab biosimilars may beunlikely to be prescribed by most gastroenterologists “due to the lackof clinical data in inflammatory bowel disease”, according to a surveyby market researcher BioTrends Research. “Over 70% of surveyedgastroenterologists would not use biosimilar infliximab in Crohn’sdisease or ulcerative colitis patients if the clinical trial had only beenconducted in rheumatoid arthritis patients,” the study concluded.Hospira’s Inflectra and Celltrion’s Remsima biosimilars of infliximabrecently received approval from the European Commission (Genericsbulletin, 20 September 2013, page 17).

PAR has begun shipping a generic version of Pfizer’s Glucotrol XL(glipizide) extended-release tablets in the US after receiving finalapproval from the country’s Food and Drug Administration (FDA).The diabetes drug is available in 5mg and 10mg strengths. CitingIMS Health data, Par said these two strengths of glipizide had annualUS sales of around US$89 million.

BIOOUTSOURCE says it has “consolidated its position as theleading expert in the biological analysis of biosimilar monoclonalantibodies” after investing in “the creation and launch of a widerange of off-the-shelf testing methodologies to support comparability,stability and lot-release testing for biosimilars”. The UK-basedprovider of contract-testing services said its “extensive experiencein developing and validating cell-based assays” could “significantlyreduce the time and cost of biosimilar development programmes”.“We are continuing to invest and expand our testing capabilitiesin Glasgow, Scotland, and are significantly increasing commercialactivities in the North American and Asia-Pacific regions,”BioOutsource stated, adding that it was “working with more than30 of the top biosimilar players globally”. G

IN BRIEF

Teva has been granted US Food and Drug Administration (FDA)approval for the country’s first generic version of Roche’s Xeloda

(capecitabine) 150mg and 500mg tablets. While six-month paediatricexclusivity for the only patent listed against the oncology brand in theFDA’s Orange Book – US patent 5,472,949 – runs until 14 June nextyear, patent litigation in a New Jersey district court has been dismissed.

At the same time, the agency has approved a new formulationof Teva’s Treanda (bendamustine) injectable brand through a ‘priorityreview’ of the firm’s supplemental new drug application (sNDA). “Thisnew liquid formulation removes the step of reconstituting lyophilisedpowder with sterile water prior to adding the medicine to the dilutent,”the Israeli firm explained.

Teva has also agreed a “multi-project alliance” with CancerResearch Technology (CRT), the technology development arm ofBritish charity Cancer Research UK. G

ONCOLOGY DRUGS

Teva has first US Xeloda rival


PRODUCT NEWS


Stada has expanded its range of Alzheimer’s disease treatments inSpain by launching generic galantamine capsules, memantine

tablets and rivastigmine transdermal patches. The new additions to thefirm’s portfolio accompany existing Alzheimer’s disease treatmentsoffered by Stada’s Spanish subsidiary, such as donepezil tablets andorodispersible tablets, and rivastigmine in the form of oral solution.

Noting that its galantamine capsules were equivalent to Janssen’sReminyl brand, Stada added that the product was available in 8mg,16mg and 24mg strengths. Meanwhile, the firm pointed out, itsmemantine tablets in 10mg and 20mg strengths were rivals toLundbeck’s Ebixa. Finally, Stada observed, its rivastigmine patcheswere equivalent to Novartis’ Exelon and were marketed in 4.6mg/24hours and 9.5mg/24 hours strengths.

“These three new generic drugs are very important to ourcommitment and leadership strategy in the area of Alzheimer’s disease,stated Stada Spain’s director general, Mar Fábregas. Insisting that “newgeneric drugs recently introduced in the Alzheimer’s area have producedsubstantial progress in access to treatment of this disease”, Fábregasadded that generic versions of donepezil, galantamine, memantine andrivastigmine held the potential to save Spain’s healthcare system aroundC150 million (US$203 million) annually.

Meanwhile, Stada has lent its support to a website aimed ateducating and informing Spanish patients about Alzheimer’s disease. G

ALZHEIMER’S DISEASE DRUGS

Stada Spain adds toAlzheimer’s portfolio

An injunction that prevented Teva from marketing irbesartan/hydrochlorothiazide tablets in the Netherlands has been overturned

on appeal. The ruling by a court in The Hague came just weeks beforethe supplementary protection certificate (SPC) at the centre of thedispute expires this month.

A year ago, Sanofi had persuaded a district court judge in TheHague to award a provisional injunction preventing Teva from marketingits version of the originator’s CoAprovel combination tablets. Theinjunction remained in effect pending further hearings on Sanofi’sDutch SPC 990,006, which runs until 14 October 2013 (Genericsbulletin, 14 September 2012, page 17).

Sanofi’s combination SPC, the Dutch court noted, was based onthe local part of European patent EP0,454,511, which expired in March2011. However, the ‘511 patent had already served as the basic patenton which the expired Dutch SPC 980,039 – protecting mono formsof irbesartan – was based.

Referring to European Court of Justice (ECJ) jurisprudence,The Hague court ruled that only one SPC was permitted per basicpatent. Therefore the combination SPC – issued after the ‘039 monoSPC – was likely to be found invalid at full trial. Pending a finalruling, the court forbade Sanofi from any actions that could hindersales of Irbesartan/HCT Teva tablets.

Having since late-2009 held marketing authorisations for irbesartan/hydrochlorothiazide (Generics bulletin, 16 October 2009, page 11),Teva secured a listing for the antihypertensive on the Netherlands’G-Standaard prescribing database in August last year. G

ANTIHYPERTENSIVES

Teva defeats DutchCoAprovel injunction

Mylan has launched the first generic rival in the US to Pfizer’sVfend (voriconazole) 40mg/ml oral suspension following approval

from the US Food and Drug Administration (FDA). The US firm isentitled to 180-day exclusivity, having been the first firm to file anabbreviated new drug application (ANDA) containing a paragraph IVpatent certification for the antifungal agent.

Citing IMS Health data, Mylan said US sales of voriconazole40mg/ml oral suspension were US$17.1 million in the 12 monthsended 30 June 2013.

The launch extends the range of voriconazole formulations soldby Mylan. After entering into a litigation-settlement and licenceagreement with Pfizer in 2009, the generics firm was first to marketin 2011 with voriconazole 50mg and 200mg tablets (Generics bulletin,4 March 2011, page 20). G

ANTIFUNGALS

Mylan claims antifungal first

Canadian generics firms are not entitled to disgorgement oforiginators’ sales or profits when the former engage in patent

litigation, a Court of Appeal in Ontario has stated. Apotex had sought toreclaim a share of proceeds from Abbott and Takeda from sales ofPrevacid (lansoprazole) after the three firms had settled litigation. G

PATENT LITIGATION

Ontario court denies damages


PRODUCT NEWS


Sandoz has blunted the advantage Dr Reddy’s had gained throughthe first US approval of a generic version of Celgene’s Vidaza

(azacitidine) brand. Through a deal with the originator, Sandoz haslaunched an authorised generic of the injectable treatment for thebone-marrow disease myelodysplastic syndrome.

Both Sandoz and Reddy’s are offering 100mg single-use vials,the same strength as Celgene’s Vidaza, which generates annual USsales of around US$375 million, according to IMS Health data.

Sandoz’ launch announcement came a week after Reddy’s hadsecured final approval from the US Food and Drug Administration(FDA). The Indian firm said it would introduce the drug “in the nearterm”. The FDA’s Orange Book does not list any unexpired patentsor exclusivity periods against Vidaza. G

ONCOLOGY DRUGS

Sandoz and Reddy’sbattle on azacitidine

Teva has won a US district court victory over its rivals Mylan andSandoz in a dispute over a method-of-use patent that protects the

Israeli firm’s Azilect (rasagiline) tablets until February 2017.Judge Claire Cecchi found that US patent 5,453,446 was valid

as prior art did not render it obvious, and the patent’s specification wassufficiently enabling to suggest utility to a person skilled in the art.Mylan had already admitted infringement.

Addressing Mylan’s obviousness arguments, Cecchi said that “thedifferences between the prior art and the invention covered by the ‘446patent are significant”. Only with “hindsight bias” would a skilledperson have selected rasagiline or related compounds as a potentialtreatment for Parkinson’s disease, she stated, adding that secondaryconsiderations such as commercial success – with annual US sales ofAzilect totalling around US$168 million – supported this conclusion.

On enablement and utility, Cecchi said the in vitro and in vivoresults of animal tests disclosed in the ‘446 patent were sufficientto defeat Mylan’s arguments.

Sandoz had agreed to be bound by a final judgement in Teva’scase against Mylan. Earlier this year, the Israeli firm had reachedpatent-litigation settlements with Actavis, Apotex and Orchid.

Meanwhile, Teva has launched with 180-day exclusivity genericversions of AbbVie’s Niaspan (niacin) extended-release tablets andAstellas’ Adenoscan (adenosine) vials in the US.

Teva gained two abbreviated new drug applications (ANDAs)for niacin 500mg, 750mg and 1,000mg extended-release tablets throughits takeover of Barr. A 30-month stay on ANDA approval imposedafter Barr challenged three Niaspan patents – one of which expiredon 20 September this year, while the other two expire in 2017 –ended in March 2005. Approval for Barr’s ANDAs followed in April2005, but several Niaspan patents protected the brand until Tevaannounced its launch on 20 September this year. Citing IMS Healthdata, the Israeli firm said Niaspan achieved US sales of US$1.12billion in the year ended June 2013.

In the same period, US sales of Adenoscan – a cardiovascular drugused as an adjunct to myocardial perfusion scintigraphy – totalledUS$65 million. Teva secured 180-day exclusivity for its 60mg/20mland 90mg/30ml single-dose vials by virtue of its challenge to US patent5,731,296, which expires on 24 March 2015. Litigation over the‘296 patent was dismissed in 2007. G

PARKINSON’S DISEASE DRUGS

Teva beats rivals onAzilect patent in US

Amgen has kicked off a randomised, double-blind Phase III clinicaltrial to compare the efficacy and safety of its ABP 501 biosimilar

candidate to AbbVie’s Humira (adalimumab), according to an entryin the European Union’s (EU’s) clinical trials register.

The primary endpoint for efficacy will be a 20% improvement atweek 24 of a set of diagnostic measurements defined by the AmericanCollege of Rheumatology (ACR20). In total, 500 adults with moderateto severe rheumatoid arthritis will participate, spread across 70 sitesin the European Economic Area (EEA), as well as other locations inArgentina, Canada, Mexico, Russia and the US. G

BIOSIMILARS

Amgen studies adalimumab

German health insurance funds are risking product shortages bypaying just C0.21 (US$0.28) per methotrexate 5mg vial, German

generics association Pro Generika has warned. This low reimbursementprice, the association said, fell well short of covering the sterileproduction, quality-control, storage and distribution of the injectablecancer and rheumatoid arthritis treatment.

“This example,” argued Pro Generika, “shows that the price andrebate pressure for many molecules is so high that generics firms cannoteconomically offer products the funds consider to be invaluable.”G

ONCOLOGY DRUGS/ARTHRITIS DRUGS

Germany underpays for vials

Glenmark Generics has secured US approvals for generic versions ofAstellas’ Locoid Lipocream (hydrocortisone butyrate) 0.1% cream

and Taro’s Topicort (desoximetasone) 0.25% ointment. While the Indianfirm has immediately started shipping its rival to the Topicort dermatosestreatment, it will be able to launch its rival to Locoid towards the end ofthis year under the terms of a patent-litigation settlement that Glenmarksays should give it 180-day exclusivity for the dermatoses brand. G

DERMATOLOGY DRUGS

Glenmark gains US topicals


Asummary judgement of non-infringement that Dr Reddy’s hadobtained against a key US patent protecting Sunovion’s Lunesta

(eszopiclone) sleeping aid has been overturned on appeal.A New Jersey district court had ruled that an abbreviated new drug

application (ANDA) filed by the Indian firm did not infringe key claimsof US patent 6,444,673. According to the district court, the phrase“essentially free” used in the patent meant containing “less than 0.25%of the laevorotatory isomer”. As Reddy’s had stated that its eszopiclonetablets would contain “not less than 0.3%” of the laevorotatory isomer,a summary judgement of non-infringement was appropriate.

But the US Court of Appeals disagreed. “We affirm the districtcourt’s construction of the claim term ‘essentially free’ as containingless than 0.25% laevorotatory isomer,” the appeals judges said.

However, they pointed out, an amended ANDA filed by Reddy’shad sought approval for the dextrorotatory isomer eszopiclone with a0.0% to 0.6% impurity of laevorotatory isomer. Irrespective of the Indianfirm’s assurances that its internal manufacturing guidelines wouldensure the generic tablets contained at least 0.3% of the impurity, thegeneric fell within the claims of the ‘673 patent which expires next year.

If an ANDA product submitted for US approval fell within the scopeof an issued patent, “a judgement of infringement must necessarilyensue”, the appeals judges concluded. “Simply saying ‘But I won’tdo it’ is not enough to avoid infringement.” G

PRODUCT NEWS


TEVA has launched its Quartette (levonorgestrel/ethinylestradiol)prescription oral contraceptive in the US after receiving approvalfrom the country’s Food and Drug Administration (FDA). “Quartetterepresents the only extended-regimen oral contraceptive approvedby the FDA with an ascending dose of oestrogen, designed to providewomen with four short, light periods per year,” the Israeli firm stated.It is offering a ‘Quartette savings card’ and operating a dedicatedproduct website to promote the brand.

ACTAVIS has launched a generic alternative to Pfizer’s Xalacom(latanoprost/timolol) 50µg/5mg/ml ophthalmic solution in Francethrough the generics firm’s Arrow subsidiary. The product is alreadylisted in the country’s répertoire of equivalents. At the same time,Actavis has launched fosinopril/hydrochlorothiazide 20mg/12.5mgtablets that are equivalent to Merck’s Foziretic brand and are alsoincluded in the répertoire.

RANBAXY says it plans to “vigorously defend” itself against aparagraph IV challenge to its Absorica (isotretinoin) capsules inthe US by Actavis. Having received notice from Actavis that the firmhad filed an abbreviated new drug application (ANDA) challengingtwo patents protecting the dermatology brand until September 2021,Ranbaxy said it would “pursue all available legal and regulatorypathways in defence of the product”. The Indian firm licenses thebrand from Cipher Pharmaceuticals.

AMERIGEN’s Chinese subsidiary, Suzhou Amerigen Pharmaceuticals,has struck a marketing and distribution deal with local firm SinochemJiangsu Pharmaceutical for Amerigen’s mecobalamin 0.5mg tablets.Amerigen will manufacture the product at its facility in Suzhou,China – which has been approved by both the US Food and DrugAdministration (FDA) and China’s Food and Drug Administration(CFDA) – while Sinochem will have “exclusive sales and distributionrights” in China in exchange for undisclosed payments to Amerigen.The first shipments – which will be sold under Suzhou Amerigen’slabel – are due in mid-2014.

WOCKHARDT has been sued by Novartis’Alcon eyecare subsidiaryin the US over the generics firm’s paragraph IV abbreviated newdrug application (ANDA) for a rival to the brand company’s Pataday(olopatadine) ophthalmic solution. The originator is seeking adeclaratory judgement from an Indiana district court that Wockhardt’sANDA infringes two patents protecting the brand up to 2024.

TGA – Australia’s Therapeutic Goods Administration – has statedthat painkillers containing dextropropoxyphene will only be ableto be dispensed by pharmacists if they have seen a form signed by adoctor or dentist confirming the suitability of the product to treatthe patient. The move follows a series of decisions by Australia’sAdministrative Appeals Tribunal (AAT) rejecting the TGA’s plans towithdraw such products from the market, but introducing conditionsfor their use. “A number of countries have withdrawn approval fordextropropoxyphene-containing medicines,” the TGA observed,“including the US, Canada, New Zealand, the UK, the EuropeanUnion, Singapore, South Africa and India.”

ACTAVIS is being sued by Ferring in the US over claims thattranexamic acid 650mg tablets marketed by the generics firm infringepatents protecting Ferring’s Lysteda brand. The originator is claimingdamages of “at least US$150 million” after Watson “substantiallyand irreparably harmed the market for Lysteda” by launching afterreceiving approval from the US Food and Drug Administration(FDA) in January 2013. G

IN BRIEFSLEEPING AIDS

Reddy’s Lunesta winis reversed on appeal

South Africa’s Aspen has agreed to pay £700 million (US$1.14billion) in cash for GlaxoSmithKline’s (GSK’s) Arixtra

(fondaparinux) and Fraxiparine/Fraxodi (nadroparin) anticoagulantbrands and an associated production site. The deal – which also includesAspen taking on 400 sales and marketing staff to promote the injectablebrands in Europe and the Commonwealth of Independent States (CIS) –comprises £505 million for the brand rights, £95 million for the sterilesmanufacturing plant in Notre-Dame de Bondeville, France, and£100 million for acquired inventory.

In the 12 months ended 30 June 2013, the acquired assets generateda turnover of £366 million and a gross margin of 43%. Aspen notedthat margins had been hit by generic competition to Arixtra in the USand higher raw-material costs for Fraxiparine.

Aspen gains global rights to the brands, other than in China, Indiaand Pakistan, and will use GSK as its local distributor in Indonesia(Generics bulletin, 28 June 2013, page 5). The deal should be largelycompleted this year, with the French site to change hands in 2014.

Meanwhile, the South African firm has finalised its purchase ofMerck’s active pharmaceutical ingredients (API) facility in Oss, TheNetherlands, and at the same time has reached an option for a portfolioof 11 branded drugs. Aspen intends to use the API facility to make drugssuch as nadroparin (Generics bulletin, 20 September 2013, page 4).G

HELVEPHARM has obtained a Swiss marketing authorisation forcapecitabine 150mg and 500mg film-coated tablets. G

IN BRIEF

ANTICOAGULANTS

Aspen buys brands from GSK


Hanmi Pharmaceutical and its partner Amneal have been blockedfrom launching esomeprazole strontium tablets in the US.

AstraZeneca, the owner of the Nexium (esomeprazole magnesium)brand, said it had obtained a temporary injunction from the US Courtof Appeals, while it challenges a claim-construction ruling.

Earlier this year, Hanmi and Amneal had struck a settlementagreement whereby they conceded that AstraZeneca’s US patents5,714,504 and 5,877,192 were valid and enforceable (Generics bulletin,28 June 2013, page 23). Under the terms of the deal, a consentjudgement entered into a New Jersey district court acknowledged thatpatents protecting the brand were valid, but stated that Hanmi’s productdid not infringe the patents based on a 2012 claim-construction ruling.

In July, the originator filed an appeal against the district court’sclaim-construction finding, as permitted by the settlement. Hanmireceived US Food and Drug Administration (FDA) approval for its505(b)(2) hybrid new drug application (NDA) on 6 August, potentiallyopening the way for Amneal to launch the strontium salt.

Under the terms of a 2008 settlement with AstraZeneca, Ranbaxycurrently has the right to launch its generic version of Nexium underlicence from the originator on 27 May 2014 with 180-day exclusivity(Generics bulletin, 2 May 2008, page 11). However, Sandoz haschallenged the Indian firm’s entitlement to exclusivity after claimingthe generic took too long to obtain tentative FDA approval. G

PRODUCT NEWS


GASTROINTESTINAL DRUGS

US court bars Hanmion esomeprazole rival

Sandoz has chosen the UK to lead the global roll-out of its SurePaldelivery device for the firm’s Omnitrope (somatropin) human

growth hormone. The delivery device, which Sandoz designed in-house,has been CE-marked in accordance with European Union (EU) ruleson medical devices, and the company is awaiting similar approval fromthe US Food and Drug Administration (FDA).

SurePal offers “cartridges that require no reconstitution or priming,and a sliding injection button that requires minimum force to operate”.The device’s safety features, Sandoz said, include: non-interchangeable,dose-specific cartridges; a dose-memory function that remembers thepatient’s daily dose; and a needle hider to help reduce anxiety inpatients who are afraid of needles. G

BIOSIMILARS

Device for Omnitropemakes debut in UK

Perrigo has started shipping in the US an equivalent to Arbor’sNitrolingual Pumpspray (nitroglycerin) 400µg/spray. The generics

firm holds 180-day exclusivity for the acute treatment for angina pectoris– which has annual US sales of US$65 million – due to its paragraph IVchallenge to US patent 7,872,049, which expires on 14 March 2028.G

CARDIOVASCULAR DRUGS

Perrigo ships US angina pump


EVENTS


15-17 October

■ 14th Annual Businessof BiosimilarsBoston, USAPreceded by a one-day workshop lookingat regulatory issues, this event will covertopics such as the European Union market,policy making and clinical development.

Contact: IIR USA.Tel: +1 888 670 8200.E-mail: [email protected]: www.biosimilarsevent.com.

16-18 October

■ 10th TOPRAAnnual SymposiumLisbon, PortugalHeld in conjunction with Infarmed, thisthree-day forum will look at regulatoryissues within the generics industry. Thepharmaceutical sessions will look at issuesincluding clinical trials, the centralisedprocedure and bulk drugs.

Contact: Topra.Tel: +44 207 510 2560.E-mail: [email protected]: www.topra.org.

21 October

■ CPhI Pre-ConnectConferenceFrankfurt, GermanyTaking place the day before CPhI Worldwideand in the same location, this conferencewill provide information on generics andsupergenerics in emerging markets,development of biosimilars and biobetters,and strategic partnering.

Contact: UBM Information.Tel: +44 207 921 8039.E-mail: [email protected]: www.cphi.com.

22-24 October

■ CPhI WorldwideFrankfurt, GermanyCPhI Worldwide is a three-day exhibitionand networking opportunity which willalso include the co-located events iCSE,P-MEC and Innopack.

Contact: UBM Information.Tel: +44 207 921 8039.E-mail: [email protected]: www.cphi.com.

28-30 October

■ GPhA 2013 FallTechnical ConferenceMaryland, USAWith presentations from US Food and

Drug Administration (FDA)representatives, this three-day meeting ofthe US Generic PharmaceuticalAssociation (GPhA) will look at keyregulatory and technical issues and theirimpact on the generics industry.

Contact: GPhA.Tel: +1 202 249 7127.E-mail: [email protected]: www.gphaonline.org.

6-8 November

■ 16th APIC/CEFIC EuropeanConference on APIsMadrid, SpainThis conference will discuss the latestdevelopments in regulatory compliance.There will be representatives frominternational authorities including the FDAand the European Medicines Agency (EMA).

Contact: Concept Heidelberg.Tel: +49 6221 84 440.E-mail: [email protected]: www.api-conference.org.

11-14 November

■ 8th Generics AsiaSingaporeThis four-day event will cover issuesincluding collaborations and strategicpartnerships, market access, productportfolios, supergenerics, branding andmarketing, as well as pricing policies.There will be case studies and presentationsfrom representatives from firms includingActavis, Teva and Wockhardt.

Contact: IBC Asia.Tel: +65 6508 2401.E-mail: [email protected]: www.generics-asia.com.

12-13 November

■ 2nd Annual World BiosimilarCongress EuropeGeneva, SwitzerlandThis two-day event will discuss topicssuch as production, regulation, clinicaltrials, comparability and to-marketmodels for the international biosimilarsindustry. There will also be networking

opportunities as well as an exhibition.

Contact: Terrapinn.Tel: +44 207 092 1000.E-mail: [email protected]: www.terrapinn.com.

19-21 November

■ World Generic MedicinesCongress Americas 2013Boston, USAFocusing on issues including policy updates,IP developments, commercial strategiesfor biosimilars and building market share,this three-day event is co-located with theBiosimilar Drug Development Conference.

Contact: Health Network Communications.Tel: +44 207 608 7055.E-mail: [email protected]: www.healthnetworkcommunications.com.

25-26 November

■ EuroPLX 53Barcelona, SpainThis meeting will provide a forum in whichfirms can discuss licensing, marketing anddistribution for patented medicines, generics,biosimilars, OTC products and nutraceuticals.

Contact: Raucon.Tel: +49 6222 9807 0.E-mail: [email protected]: www.europlx.com.

22 January

■ 7th EGA PharmacovigilanceDiscussion Forum

23-24 January

■ 13th EGA Regulatory &Scientific Affairs ConferenceLondon, UKThe European Generic medicinesAssociation’s (EGA’s) PharmacovigilanceForum will precede its two-day event onRegulatory and Scientific Affairs.

Contact: Cristina Romagnoli, GPA Conferences.Tel: +377 93 501 348.E-mail: [email protected] online at www.gpaconferences.com.

9-11 December 2013

■ 16th IGPA Annual ConferenceBrussels, BelgiumThis three-day conference is being organised by the European Genericmedicines Association (EGA) and is the global event of the worldwide generics industry.It is the annual joint meeting of the Canadian, European, Japanese, South African and USgenerics industry associations, the CGPA, EGA, JGA, NAPM and GPhA.

Contact: Cristina Romagnoli, GPA Conferences. Tel: +377 93 501 348. E-mail: [email protected]: www.igpagenerics.com or www.gpaconferences.com/igpa13.htm.

NNOOVVEEMMBBEERR

OOCCTTOOBBEERR

JJAANNUUAARRYY

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PARAGRAPH IV WATCH


In US Hatch-Waxman patent-litigation cases, timing can be extremelyimportant to the bottom line for abbreviated new drug application

(ANDA) filers. The potential for 180 days of generic exclusivity for thefirst company to file a substantially complete ANDA with paragraph IVcertification that a patent is invalid, unenforceable or not infringed isa great incentive for patent challengers, and companies often take greatpains to be the first applicant. However, ‘haste makes waste’, as the oldsaying goes, and a rush to file might not pay off in the end, as HorizonPharma’s Rayos (prednisone) delayed-release tablets appear to illustrate.

Following US Food and Drug Administration (FDA) approvalof Rayos in July 2012, Horizon initially introduced its delayed-releasetablets in December last year, and conducted a full-scale launch torheumatologists and key primary-care physicians in February 2013.

Prednisone, the active ingredient in Rayos, has been approved inthe US for many years, so no New Chemical Entity (NCE) exclusivityprevented the submission of ANDAs for generic versions of the approvedbrand. According to the FDA, the first ANDA for a rival to Rayos wassubmitted on 26 November 2012 (see Figure 1).

Although the submission date ultimately determines first-to-filestatus, the Hatch-Waxman Act requires the ANDA to be accepted forfiling by the FDA before the applicant notifies the brand and patentowners of the patent challenge. If the ANDA is incomplete or presentssome other problem that must be addressed by the applicant beforethe application can be reviewed, acceptance for filing may be delayedor refused. It appears that this might have been the case with at leastone application for a generic version of Rayos.

Horizon says it received notification on 13 March 2013 of AlvogenPine Brook’s ANDA containing a paragraph IV certification to Rayospatents. At that time, the originator claims, Alvogen acknowledgedthat the FDA had not yet accepted its ANDA for review and that theletter did not constitute notice under the statute. Proper notice wouldtrigger a 45-day period in which Horizon could sue and obtain a30-month stay of approval for Alvogen’s ANDA. At present, it seemsthat no litigation has yet been initiated in response to Alvogen’s ANDA,according to Thomson Reuters, which compiles a database of paragraphIV challenges and associated litigation.

A few months later, on 15 July, Horizon received a paragraph IVnotification for an ANDA submitted by Actavis, which ThomsonReuters says ranks second only to Teva in terms of the number ofmolecules it has subjected to paragraph IV challenges (see Figure 2).In response, on 26 August, Horizon and patent-owner Jagotec filed asuit in a New Jersey district court alleging infringement of five patents,triggering an automatic 30-month stay on approval for Actavis’ANDA.

Two of those five patents – both of which expire in April 2024 –cover all three strengths of prednisone delayed-release tablets. Anothertwo patents protect just the two lower strengths, and a fifth patentsolely the 5mg version of Rayos.

In a subsequent press release, Actavis stated that, based on availableinformation, it believed it might have been the first applicant to filea paragraph IV challenge to patents protecting the anti-inflammatoryand immunosuppressive agent, and could thus be entitled to 180days of exclusivity upon launch of its 1mg, 2mg and 5mg delayed-release tablets (Generics bulletin, 6 September 2013, page 20).

“Given the timeline in the case, it is unclear to an outside observer

exactly when Alvogen may have submitted its ANDA, or why thecompany might have chosen to notify Horizon of its patent challengebefore the ANDA was accepted for filing,” comments ThomsonReuters. “It is possible that some difficulty with the application hasprevented acceptance for filing by the FDA, and thus Alvogen’schance at the 180-day exclusivity.” G

Rayos raises issue of ANDA acceptanceKEY DETAILS: RAYOS

Brand: RayosActive ingredient: prednisoneDelivery form: 1mg, 2mg and 5mg

delayed-release tablets

Brand owner: Horizon Pharma

First paragraph IV filing 26 November 2012submitted to FDA:

Known paragraph IV filers: Alvogen Pine Brook; Actavis/Watson

Patents at issue – 6,488,960* – 14 March 20206,677,326* – 14 March 20208,309,124 – 23 April 20248,394,407 – 23 April 20248,168,218** – 7 January 2028

District court location: New Jersey

Litigation reference: Horizon vs Watson et al. – 1:13-cv-05124

* listed only against the 1mg and 2mg strengths ** listed only against the 5mg strength

Figure 1: Paragraph IV challenges to Horizon’s Rayos (prednisolone) delayed-releasetablets (Source – Thomson Reuters)

Thomson Reuters draws on strategic intelligence and competitive analysis information on the US genericsindustry to create Newport Premium™, the critical product-targeting and global business-development systemfrom the industry authority on the global generics market.

For further details contact Benjamin Burck, Thomson Reuters API Intelligence, 215 Commercial Street, Portland, Maine 04101, USA.Tel: +1 207 871 9700 x35. Fax: +1 207 871 9800. E-mail: [email protected]. Website: scientific.thomsonreuters.com/newport.

Figure 2: Numbers of compounds subject to patent challenges by company, asrecorded by Thomson Reuters to 30 June 2013 (Source – Thomson Reuters)

180

160

140

120

100

80

60

40

20

0

Num

ber

ofpa

tent

chal

leng

es

PATENT CHALLENGES

Teva

Actavis

Mylan

Sandoz

Apotex

Sun Pharma

ParLupin

Dr Reddy’s

Ranbax

y

Perrigo

172

141136 135

100

82

68 65 64

443941

Aurobindo

38

Impax

Gen 4/10/13 - Pg. 21_Layout 1 02/10/2013 19:08 Page 3

Analysethe past…

Deliverthe future

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ToolboxA4leaflet-.indd 1 21/05/2013 10:54

PRICE WATCH ............ UK


Average price changes among our ‘fast movers’ were relatively smalllast month, with all but one in single digits (see Figure 1). However,

much larger changes were apparent for the lowest prices as supplierswithdrew some of their best offers.

Mycophenolate 500mg tablets in 50-count packs, for example,could not be obtained by independent pharmacists and dispensing doctorsfor less than £8.99 (US$14.40) after a 40% price hike, while the bestprice for 60-tablet packs of risperidone 2mg was 39% higher at £1.04.Falls in lowest prices were less dramatic, although deals for both28-tablet packs of nebivolol 5mg and of pioglitazone 15mg werepotentially 16% lower in September than they had been in August.

The same pattern of price rises exceeding price cuts was apparentin our wider basket of commonly-dispensed generics. Two of the

‘biggest fallers’ in Figure 2 were sertraline 50mg and 100mg, but theiraverage prices were only 28% and 22% lower. Average propanololprices, in contrast, rose by as much as 88% (see Figure 3).

Isosorbide recently experienced dramatic price rises followingshortages (Generics bulletin, 20 September 2013, page 23). The 20mgstrength features in Figure 2 with a 25% average price fall, but the 10mgand 40mg strengths were both just outside the table with falls of 11%.Nevertheless, isosorbide was still granted price concessions in Septemberin excess of Drug Tariff prices. Against average trade prices of £6.93for the 20mg strength, £8.32 for the 10mg version and £15.53 forisosorbide 40mg, all in 56-tablet packs, the Department of Health wasprepared to reimburse £5.97, £8.55 and £15.95, which would have leftpharmacists out of pocket for dispensing the 20mg variant. G

BIGGEST RISERS

Product/Strength/Pack size Lowest Change Average Changeprice (%) price (%)

Propranolol tabs 40mg 28 £0.24 +14 £1.10 +88

Propranolol tabs 10mg 28 £0.17 +6 £0.37 +50

Prednisolone tabs 5mg 28 £0.26 +4 £0.66 +47

Furosemide tabs 40mg 28 £0.12 ±0 £0.24 +44

Phenobarbital tabs 60mg 28 £0.42 ±0 £2.98 +44

Prednisolone tabs 1mg 28 £0.16 ±0 £0.40 +44

BIGGEST FALLERS


Sertraline tabs 50mg 28 £1.49 -9 £3.26 -28

Isosorbide mononitrate tabs 20mg 56 £5.45 -9 £6.93 -25

Sertraline 100mg 28 £2.08 ±0 £4.37 -22

Quinapril tabs 5mg 28 £0.75 +12 £1.71 -22

Quinapril tabs 10mg 28 £0.89 +6 £1.63 -20

Bumetanide tabs 1mg 28 £0.65 -2 £0.88 -18

Figure 1 (below): Comparison between the periods 1-31 August 2013 and 1-25September 2013 of the lowest and average UK trade prices of fast-moving generics.Each average price was calculated from at least 18 data points. Figure 2 (above)and Figure 3 (above right): Biggest changes recorded between the periods 1-31

August 2013 and 1-25 September 2013 in lowest and average UK trade prices ofabout 748 commonly-dispensed generics. The basket specifically excludes the ‘fastmovers’ shown below, but includes other presentations of the same products. Eachaverage price was calculated from at least 11 data points (Source – WaveData).

Detailed product price comparisons and other price analyses areavailable at www.wavedata.net.

To find out more about subscribing, please email your contact details [email protected] and quote ‘GB online enquiry’ in the title line.

■ For further information see www.wavedata.co.uk.Alternatively, contact Charles Joynson atWaveData Limited, UK. Tel: +44 (0)1702 425125.E-mail [email protected].

WANT MORE LIKE THIS?

FAST MOVERS


Alfuzosin tabs 2.5mg 60 £3.95 -2 £4.80 -3Anastrozole tabs 1mg 28 £1.09 -8 £2.61 -5Atorvastatin tabs 20mg 28 £0.49 -6 £0.71 -6Bicalutamide tabs 50mg 28 £1.28 -1 £2.62 +6Buprenorphine tabs 2mg 7 £1.47 -13 £2.09 -1Candesartan tabs 8mg 28 £0.89 -7 £1.24 -3Clopidogrel tabs 75mg 28 £1.10 +15 £1.36 -4Cyclizine tabs 50mg 100 £10.05 -4 £11.68 -1Desloratadine tabs 5mg 30 £0.85 -2 £1.12 -4Donepezil tabs 10mg 28 £0.62 +9 £1.50 +3Dorzolamide eye drops 2% 5ml £1.15 -7 £1.71 -7Entacapone tabs 200mg 30 £6.15 -5 £8.01 -1Esomeprazole tabs 40mg 28 £3.95 -1 £5.42 -3Exemestane tabs 25mg 30 £2.95 +4 £5.26 +2Finasteride tabs 5mg 28 £0.68 +10 £0.96 +2Irbesartan tabs 75mg 28 £0.64 +3 £0.80 -4Latanoprost eye drops .005% 2.5ml £0.82 -9 £1.42 +7Lercanidipine tabs 10mg 28 £0.61 -5 £1.05 +3Letrozole tabs 2.5mg 14 £0.80 +19 £1.42 +16Levetiracetam tabs 500mg 60 £0.99 +5 £3.31 +7Losartan tabs 100mg 28 £0.55 +12 £0.89 +2Montelukast tabs 10mg 28 £1.45 -1 £1.87 -2Mycophenolate tabs 500mg 50 £8.99 +40 £9.91 +4Naratriptan tabs 2.5mg 6 £0.69 -5 £1.42 -3Nebivolol tabs 5mg 28 £0.71 -16 £1.22 ±0

FAST MOVERS


Olanzapine tabs 5mg 28 £0.39 -5 £0.74 -6Pioglitazone tabs 15mg 28 £0.57 -16 £1.02 -7Pramipexole tabs 700µg 30 £1.66 +33 £2.97 -1Quetiapine tabs 25mg 60 £0.64 -7 £1.08 -1Rabeprazole tabs 10mg 28 £1.99 +8 £2.34 -3Riluzole tabs 50mg 56 £39.00 -5 £51.55 -3Risedronate tabs 35mg 4 £0.48 +9 £0.69 +1Risperidone tabs 2mg 60 £1.04 +39 £1.83 +5Terbinafine cream 1% 15g £1.21 +2 £1.50 -1Tolterodine tabs 2mg 56 £1.90 -4 £2.88 -1Topiramate tabs 25mg 60 £0.88 ±0 £1.82 +7Trandolapril caps 2mg 28 £0.97 ±0 £1.40 -1Valsartan caps 80mg 28 £0.84 -6 £1.31 -5Venlafaxine tabs 75mg 56 £1.60 +2 £2.14 -2Zolmitriptan tabs 2.5mg 6 £0.50 +11 £1.01 -1

Fast movers feature minor price changes


In the medical world, ultrasound is best known as ameans for providing pregnancy scans or diagnosinginjuries. But a mile or two from Oxford’s university

colleges, UK-based firm Prosonix is using ultrasoundtechnology to overcome development challenges informulating respiratory drugs. As it prepares to filein Europe during next year for a generic version ofGlaxoSmithKline’s (GSK’s) Flixotide/Flovent(fluticasone propionate) – and with several other projectsin development – the firm is discussing marketing dealswith many of the industry’s leading lights.

Employing an ethos of “Respiratory Medicine byDesign”, Prosonix says its particle-engineering technologycan make active pharmaceutical ingredients (APIs) thatcan be delivered through both off-the-shelf pressurisedmetered-dose inhalers (pMDIs) and dry-powder inhalers(DPIs) in forms that are equivalent to original drugs.

“If you do not have a technical advantage on theAPI, I think you will struggle to succeed,” Prosonix’chief executive officer and co-founder David Hipkisstold Generics bulletin during an exclusive interview.

“In the classical generics world,” Hipkiss said, “thereis always an expectation that a product can be made, butthat is a gross over-simplification when it comes torespiratory products.” By engineering particles’ physio-chemical properties through ultrasound, he said, Prosonixhas made respiratory APIs “right first time” and hasovercome the innate variability and lack of stability thatcauses many API and finished-dose batches to be rejected.

Along with business partner Andy Bush – nowProsonix’ chief operating officer and chief financialofficer – Hipkiss in early 2006 led a spin-out fromprivate-equity fund Coller Capital. Coller had pickedup the ultrasound technology as part of its acquisition

of Accentus, a subsidiary of the UK Atomic EnergyAuthority offshoot AEA Technology.

Hipkiss joined AEA as global licensing director inpart to capitalise on a neglected technology – usingultrasonic wave energy to govern and improve APIcrystallisation through nucleation control. “I gave myselftwo years to get the technology, but it took me four,”he commented. Since then, Prosonix has raised morethan £22 million (US$35 million) from leading Europeanventure-capital funds, and has formed several respiratorycollaborations, including with top universities.

Having proved its ultrasound technology on acommercial scale – not least by helping aluminaproducers to remove impurities through crystallisation –Prosonix is now focusing on developing and licensingrespiratory drugs. “This is not a technology dream, thisis commercial reality,” Hipkiss stressed. “Our engineeredAPIs are being produced at a global scale in facilitiesaudited by the US Food and Drug Administration (FDA).”

Development work and early-stage testing isconducted at the firm’s Oxford headquarters, beforetechnology is transferred to partners, such as steroidalAPI firm Sterling’s site in Italy.

“Current inhaled corticosteroid (ICS), long-actingbeta agonist (LABA) and long-acting muscarinic agonist(LAMA) mono and combination therapies are welldefined, safe and effective for most patients,” Hipkissasserted. “Industry has to question whether it is worthspending the up to US$4 billion PWC recently said itcosts today to take a new molecule to market.”

Amid extended austerity measures and ever-changingreimbursement models, governments would examinehow to reduce the reimbursement burden from chronicconditions such as asthma and chronic obstructive

BUSINESS STRATEGY


UK-based respiratory

specialist Prosonix is

talking to prospective

partners about

marketing generics

and supergenerics made

using its ultrasonic,

particle-engineering

technologies.

Aidan Fry reports.

Prosonix sounds out optionsfor its respiratory platform

Project Active Region Device Development stagereference ingredient/s type

PSX1001 Fluticasone propionate EU pMDI suspension Targetting decentralised submission in secondquarter of 2014, based purely on in vitrobioequivalence

PSX1050 Fluticasone propionate US pMDI suspension Targetting ANDA submission, awaiting FDAdose counter meeting to discuss clinical trial programme

PSX2005 Fluticasone/salmeterol EU pMDI suspension Targetting EU submission based purely ondose counter in vitro bioequivalence

PSX1442 Undisclosed EU/US Capsule-based DPI Targetting EU submission, based purely on invitro bioequivalence, with partner; targettingANDA submission in US with partner

PSX1439 Undisclosed EU pMDI Targetting EU submission, based purely onin vitro bioequivalence

PSX1002 Glycopyrronium Global multi-dose pMDI All patient dosing complete in Phase IIabromide clinical study, results expected in early 2014

PSX2000 various combinations Global pMDI/DPI Multiple chemical-pharmaceutical developmentprogrammes underway

Figure 1: Prosonix’ disclosed product pipeline (Source – Prosonix)

David Hipkiss


pulmonary disease (COPD), he believed. “There is asignificant opportunity for directly-substitutable generics,branded generics and speciality products, all enabledand optimised by particle-engineered APIs andformulations in simple, cost-effective devices,” Hipkissmaintained. Describing Prosonix as able to be “deviceagnostic”, he questioned the credibility of long-termreimbursement models involving complex devices.

But at the same time, Hipkiss acknowledged, moretechnically-informed regulatory agencies had become“razor sharp” on chemistry, manufacturing and controls(CMC) elements that defined physicochemical profilesof inhaled drugs, such as particle size, shape, surfaceproperties and aerodynamics. This, he said, presentedchallenges in proving equivalence and securing approval.“But if you can put products together in an optimumway, you can achieve equivalence and may be able toget a clinical advantage over newer moieties, becauseyou made them right first time.”

Former Watson, Pliva and Ranbaxy executiveCécile Miles – who joined Prosonix earlier this yearas chief business officer to lead the UK-based firm’spartnering and commercial operation (Generics bulletin,8 March 2013, page 26) – noted that generics companiestypically approached the respiratory sector by focusingon devices, because they assumed they knew how tohandle the drug substance and excipients. “But they arehitting the wall on the APIs,” she said.

Generics firms could purchase monograph-standardAPIs, with verified particle-size ranges, but still ran intoproblems, Miles continued. “Even if you get the rightmass of API to a site in the lung, if it is the wrongtype of particle, you may well get a different effect.Generics developers may have underestimated this atfirst,” she insisted.

Ensuring the size distribution of particles – in the2-5 micron range that could be absorbed by the lung –was crucial, but not the whole story, Miles pointed out.Equally important was controlling the shape of theparticles to determine how they were dispersed andabsorbed. Surface properties were also vital, especiallyin affecting the aerodynamic performance of APIsformulated with lactose excipients in DPI devices.

Hipkiss argues that conventional techniques forproducing respiratory APIs are sub-optimal. Typicallythese involve creating large crystals that are pulverisedthrough jet-milling to reduce particle sizes to the desired2-5 micron range. But the resulting particles were oftenunstable and variable in their performance, he said.Respiratory originators with integrated supply chainsfrom drug to device tended to manage quality througha range of in-process pass/fail tests before and afterformulation and filling. “If a batch fails, the API cannotbe recovered and the whole batch has to be scrapped.Generics firms needing to develop and produce low-cost products do not have the luxury to do that,” he said.

Furthermore, he added, the success of jet-milling– reducing particle sizes by crashing them into eachother in a chamber – depended on the surface hardnessand fragility of each molecule. While it worked well forhighly-fragile, hydrophillic substances like salbutamol,less fragile hydrophobic steroids tended to becomeamorphic under jet-milling. “LAMA drugs likeglycopyrronium are another magnitude more difficultthan steroids, while some newer molecules are so innatelyhard that they strip metal out of the mill,” he noted.

Prosonix says it has solved this problem by applyingits particle-engineering technologies. Among these isthe ‘DISCUS’ technology, standing for ‘DispersiveCrystallisation with UltraSound’. This uses soundwaves to create consistently-sized particles directlyfrom solution without the need for jet-milling. Thistechnology – particularly suited to ingredients for pMDIs –is already embedded at the firm’s production partners,including at Sterling’s FDA-approved site.

And through Prosonix’ related UMAX process –which combines spray-drying and ultrasound – the firmis able to produce spheroidal crystals that combine fixedtitratable doses of one or more APIs “in each and everyparticle”. This technology works by atomising liquidsolutions into droplets, drying them into amorphousspheres, and then supplying energy through ultrasoundto convert the spheres into highly-crystalline materialthat retains the spheroidal morphology with a high surface‘rugosity’. This roughness of surface minimises particlessticking together and ensures that particles separateefficiently from excipient carriers, such as lactose.

More than 20 patent families protect various aspectsof the firm’s intellectual property related to its pipelineof generics, supergenerics and originals.

As Figure 1 shows, the company is developingfluticasone propionate generics for both the EuropeanUnion (EU) and US as monotherapy ICS treatments forasthma and COPD that can be substituted directly forGSK’s Flixotide and Flovent brands. These will besupplied in pMDI devices. “From a regulatorystandpoint, pMDIs are easiest to substitute,” Hipkisscommented. “Unlike passive DPIs, the energy is constantand contained within the system, so they are easier todevelop and easier for the regulators to assess.”

In the EU, Prosonix plans to file for fluticasonein the second quarter of next year via the decentralisedroute. Having taken extensive scientific advice andconsulted EU guidelines, the firm believes it will obtainapproval for its PSX1001 candidate purely on the basis ofin vitro equivalence, without conducting clinical trials.

“Our regulatory batches are under stability testingin Europe,” Miles stated. “Our preference would be toreach a global agreement, and we are talking to globalplayers.” Prosonix was negotiating with parties in theUS, EU, South America and the Middle East and NorthAfrica (MENA) region, and would approach potentialpartners in Japan, she added.

Miles acknowledged that the nine largest EUmarkets accounted for less than 8% of global fluticasonesales that totalled around US$1.2 billion. But whileNorth America made up nearly 90% of total sales, shesaid countries including France and the UK, as well asAustralia, still offered attractive fluticasone markets.

A US abbreviated new drug application (ANDA)programme is underway, and Prosonix is awaiting ameeting with the FDA’s Office of Generic Drugs (OGD)on its PSX1050 candidate. Noting that the FDA wouldrequire pharmacokinetic (PK) and pharmacodynamic(PD) trials, Miles said the firm was confident that it couldmeet the agency’s ‘weight of the evidence’ approach.

Hipkiss described the FDA’s recently issued draftguidance on generic Advair (fluticasone/salmeterol) aspositive for the generics industry, although he saw it as“still a very high hurdle to clear” (Generics bulletin,20 September 2013, page 1). In the EU, Prosonix believesit will be able to get approval, as with mono fluticasone,

BUSINESS STRATEGY

“Even if you get the

right mass of API to a

site in the lung, if it is the

wrong type of particle,

you may well

get a different effect”



for the combination pMDI without doing clinical trials.Miles said pMDI forms, such as the one Prosonix

was developing, accounted for US$1.4 billion of globalfluticasone/salmeterol sales of US$9 billion. And unlikemono fluticasone, the combination pMDI was sold largelyin the EU rather than North America, with Australiaoffering a market valued at more than US$100 million.

“A US$800 million market is available via thein vitro equivalence route in the EU,” Miles pointed out.Even after Mylan’s announcement that it and partner3M had already conducted PK trials ahead of a plannedpMDI filing later this year (Generics bulletin, 9 August2013, page 23), she insisted a generic of GSK’s Seretidecombination remained an attractive partneringopportunity. “We are also considering marketing theproduct ourselves,” she added.

Prosonix’ generics pipeline also includes twoco-development deals with partners for undisclosedsingle molecules. PSX1442 is a LAMA treatment forCOPD that is delivered in a capsule-based DPI and isscheduled for an in vitro only filing in the EU as wellas an ANDA submission in the US. In vitro equivalencewill also form the basis of an EU filing for PSX1439,a LABA-based pMDI for asthma and COPD.

The company’s disclosed supergeneric candidate,PSX1002, is a multi-dose pMDI version of the capsule-based Seebri (glycopyrronium bromide) COPD treatmentthat Novartis recently launched. Having just completeda Phase IIa dosing study, Prosonix believes its pMDIversion is potentially a “best-in-class, once-daily LAMAmonotherapy for COPD” that could rival BoehringerIngelheim’s US$4 billion Spiriva (tiotropium) blockbuster.

“People with COPD are often elderly and arthritic,so getting capsules out of a blister, flipping the devicelid, loading then piercing the capsule, and then havingto inhale hard is perhaps not ideal,” noted Hipkiss.

Miles said Prosonix had already attracted stronginterest from potential partners for PSX1002, which wasbeing developed as a hybrid ‘505(b)(2)’ formulationbecause Novartis held data exclusivity for Seebri.Monotherapies like glycopyrronium, she pointed out,could also be used as adjuncts to ICS/LABA treatments.

“For COPD, a triple combination in a can is wherewe might be headed,” commented Hipkiss. Using itsUMAX technology, Prosonix is working on severalPSX2000 multi-component particle (MCP) candidatesthat could offer fixed-dose combinations in titrated dosesto be delivered through simple devices. “Uniquely wecan put two molecules in the same particle,” Hipkissclaimed, adding that delivering multiple APIs to the samesite more effectively than current heterogeneous blendsof molecules might offer improved clinical effects. “Thiswill open up a huge opportunity for branded genericswith built-in intellectual-property protection,” he added.

Noting the high level of merger and acquisitionactivity in the respiratory sector – such as AstraZeneca’sUS$1.15 billion deal for Pearl Therapeutics – Hipkisssuggested Prosonix’ long-term value might outstrip all ofits rivals due to the “breadth, robustness and commercialattractiveness” of its particle-engineering technology.

“We are the only company that can do both pMDIsand DPIs as generics, branded generics and originals,”he said. “We have the ability today to put tomorrow’streatments into devices that are affordable for all.” G

BUSINESS STRATEGY


“Uniquely we can put

two molecules in the

same particle.This will

open up a huge

opportunity for

branded generics”


Keith Webber is standing down from his position at the US Foodand Drug Administration (FDA) to join Perrigo from 21 October

as the firm’s head of regulatory review with responsibility forprescription and consumer healthcare product applications and projectsin development. On 18 October, Webber will retire from his currentrole as acting director of the Office of Pharmaceutical Science in theFDA’s Centre for Drug Evaluation and Research. The agency hasnamed Lawrence Yu as Webber’s successor.

Perrigo’s president and chief executive officer, Joe Papa, said thatin the newly created role Webber would use his industry experienceto “work closely with regulatory leadership to support new-productselection and develop strategies and processes to achieve high-qualityapplications and timely approvals”. Prior to his appointment, Webberhad held senior roles within the FDA for nearly 20 years, includingas director of the US agency’s Office of Generic Drugs.

Meanwhile, Perrigo has appointed Ann Schumar as a productionengineer and Natalie Colley as a validation engineer specialist at itsfacility in New York, US. The firm has also made John Crabill seniormanager for food safety and regulatory compliance, overseeingnutritionals made at its Gordonsville plant in Virginia, US. G

PEOPLE


APPOINTMENTS

FDA’s Webber getsnew role at Perrigo

The European Medicines Agency (EMA) has revealed a newstructure that it claims will help the organisation’s scientific

committees to keep delivering “high-quality, consistent opinions” onmedicines for human use. Built around four new “core divisions” thatcover the lifecycle of medicines from development to use in patients,the revised structure would help better support the scientific work ofthe EMA’s committees, the agency insisted, as well as improvinginformation-sharing throughout the European Union (EU).

The four new divisions are: Human Medicines Research andDevelopment Support; Human Medicines Evaluation; ProcedureManagement and Business Support; and Inspections and HumanMedicines Pharmacovigilance. These changes – due to be completed by2014 – would introduce a new operating model for how medicineswere managed throughout their entire lifecycles, the EMA pointedout, with a separation of scientific and procedure management.

As part of the restructuring, the EMA has created the roles ofchief policy adviser and head of programme design board, held byNoël Wathion and Agnès Saint Raymond respectively. G

REGULATORY AGENCIES

EMA reveals new structure

Merck KGaA’s biosimilars activities now lack a permanent headafter the German group decided to shift the current incumbent,

Thierry Hulot, to succeed Jim Stewart as head of global manufacturingand supply from 1 October. “Hulot will continue to lead the Biosimilarsunit on an interim basis until a replacement has been announced,” Merckstated. Hulot’s replacement will report directly to Pharmaceuticalshead Stefan Oschmann. G

RESHUFFLES

Merck shifts biosimilars head

We also publish OTC bulletinVisit www.OTC-bulletin.com

MEDA’s Anders Lönner is stepping down as chief executive officerof the Swedish company after 14 years in the role. He will be replacedby Jörg-Thomas Dierks, 53, who has been Meda’s chief operatingofficer since 2005.

CIPLA has announced that one of its directors, Ranjan Pai, has“resigned from the directorship of the company due to his increasingbusiness commitments”.

GMIA – Australia’s Generic Medicines industry Association – haswelcomed the appointment of Peter Dutton as the country’s healthminister. Fiona Nash will be assistant health minister. Dutton had“demonstrated a detailed understanding of the medicines industry,supporting the use of generic medicines”, the GMiA observed.

FDA – the US Food and Drug Administration – has named MelindaPlaisier as permanent associate commissioner for regulatory affairs.Plaisier had held the position on an interim basis since October 2012,when Dara Corrigan announced she would be vacating the role.

MHRA – the UK’s Medicines and Healthcare products RegulatoryAgency – is now being led by its new chief executive Ian Hudson.Earlier this year, former licensing director Hudson was appointedto take over from Sir Kent Woods, who has stepped down after 10years with the agency (Generics bulletin, 12 July 2013, page 23).

VECTURA is looking for a new non-executive chairman followingJack Cashman’s retirement after 12 years in the position. The UKfirm’s chief executive officer, Chris Blackwell, praised Cashmanfor transforming Vectura from “a small private business with a limitedpipeline into a well-financed company with multiple revenue streams”.

CELESIO has extended by five years the contracts of its chieffinancial officer, Marion Helmes, who has been the firm’s actinghead, and chief sales and marketing officer, Stephan Borchert.

NACDS – the US National Association of Chain Drug Stores – hasnamed Chris Smith as its director of federal public policy. Smithhad previously served as director of policy and regulatory affairsfor the National Community Pharmacists Association (NCPA).

PHOENIX’ chief financial officer, Michael Majerus, has left thecompany by mutual consent. He has been repaced by HelmutFischer, who was previously chief financial officer for HeidelbergCement’s operation in Dallas, US.

RITE AID has promoted Tammy Royer to group vice-presidentof managed care. Having joined the company in 1996, Royer hasheld a variety of positions both in the field and corporate office.

TARO has accepted the recommendation of Glass Lewis – one of theworld’s largest independent proxy advisory services – and re-electedIlana Avidov-Mor and Dan Biran, two of the company’s incumbentexternal directors, thwarting Raging Capital’s bid to elect Ben-AmiRosenfeld and Adi Bershadsky to the positions. At the same time,Taro re-elected Dilip Shangvi, Kal Sundaram, Sudhir Valia, JamesKedrowski and Dov Pekelman to the company’s board of directors.G

IN BRIEF


Documents

Gen 18/11/05 Pg. 1