enerics ulletin nforma - Generics Bulletin · Zentiva from Spain’s Insud Pharma, the former Chemo group of companies, where he has served as CEO since 2016. He will be based in

25 January 2019No.383

Pharma IntelligenceInformaBulletin

Genericsgener icsbul let in .pharmaintel l igence . informa.com

SABRIL

First Sabril Rival Sees FDA Deliver On Prioritizing Competition, p. 12

EUROPEAN REGULATION

European Council Brings SPC Manufacturing Waiver A Step Closer, p. 4

ALVOTECH

Alvotech Advances Partnerships To Take Pipeline Global, p. 7

Industry Veteran Haggar To Lead Private Equity-Backed Zentiva From Next MonthDEAN RUDGE [email protected]

N ick Haggar has pledged to ex-pand reach, increase productivity and accelerate growth after being

appointed chief executive officer of the newly carved-out, private equity-backed Zentiva business.

Taking up the role from 11 February, Haggar will join Czech Republic-based Zentiva from Spain’s Insud Pharma, the former Chemo group of companies, where he has served as CEO since 2016. He will be based in Prague and report to the com-pany’s advisory committee.

Haggar told Generics Bulletin, “The Zentiva opportunity is really compelling – a pan-European generics player with a strong footprint in all market archetypes, tremendous technical capability, a strong pipeline and a team that is hungry to drive growth.”

Joining Haggar at Zentiva are two se-nior industry figures. Fromer Ivax, Glen-mark, Lupin and Apotex executive Ewan Livesey is now Zentiva’s head of corpo-rate development. Based in Switzerland, Livesey will oversee business-develop-

ment activities such as licensing deals and mergers and acquisitions. Internal re-forms and restructuring will be overseen by former Cipla executive Anant Atal as chief transformation officer.

ADVENT TAKEOVER COMPLETED ON 30 SEPTEMBER

With more than 30 years of experience, Haggar has held leadership roles on both sides of the pharma industry, in-cluding with the former Ranbaxy busi-ness and GlaxoSmithKline. Before join-ing Insud in 2016, he served from 2008 to 2015 with Sandoz, including as head of Western Europe, the Middle East and Africa and the Novartis division’s global Respiratory business.

Haggar also previously served as presi-dent of European off-patent industry asso-ciation Medicines for Europe, at which time it was called the European Generic and bio-similar medicines Association (EGA).

His appointment comes just four months after Advent International completed its €1.9 billion (US$2.2 billion) acquisition from Sanofi of the Zentiva European ge-nerics business, a deal first agreed in June 2018. Talks between the two parties were confirmed months earlier (Also see “Advent firms up deal for Sanofi in Europe” - Generics Bulletin, 6 Jul, 2018.).

At the time of its acquisition, Zentiva was led by Sanofi veteran Patrick Aghanian. A Zentiva spokesperson confirmed to Ge-nerics Bulletin that Aghanian had “stepped back” from the role in November last year, weeks after the deal closed.

Shortly before his departure, Aghanian spoke exclusively with Generics Bulletin, detailing the company’s strategy as an

CONTINUED ON PAGE 4

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LEADERSHIP

Phil Jarvis

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SUBSCRIPTIONSVal Davis

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DESIGN SUPERVISORGayle Rembold Furbert

PRODUCTIONDebi Robinson

This week has seen a significant step towards a European waiver that would allow generics and biosimilars firms to manufacture during the term of supplementary protection certificates (SPCs).

An SPC manufacturing waiver has for years been an aspiration of European off-patent in-dustry association Medicines for Europe, and the European Council’s approval of a mandate for negotiations with the European Parlia-ment is the latest step in what has been a long journey towards this goal.

However, the move has not met with univer-sal approval, with European brand industry association EFPIA in particular reinforcing its opposition to such a waiver (p.4).

At the same time, the biosimilars sector has once again seen major developments. Pfizer an-nounced that it has shelved development of five pre-clinical biosimilars as it shifts its focus to late-stage innovative programs (p.6), while Alvo-tech is pushing ahead with global partnerships to market its own portfolio (p.7).

Cipla has struck a partnership with Bio-Thera for its bevacizumab biosimilar (p.12), as Belgian authorities have unveiled an incentives scheme that they hope will boost uptake for adalimumab and etanercept (p.9).

Significant movements have also been seen on small-molecule generics, with the US Food and Drug Administration (FDA) approving the country’s first rival to the Sabril (vigabatrin) epi-lepsy treatment (p.12). And intellectual-property challenges in the US have seen mixed fortunes, with Amerigen’s attack on Toviaz (fesoterodine) failing (p.13) at the same time as Teva was vin-dicated over its launch of generic Uceris (p.14).

Meanwhile, Zentiva has named industry vet-eran Nick Haggar to lead the company as chief executive officer from February. Known to many for his work at Sandoz and Insud, as well as for his tenure as president of Medicines for Europe in its former incarnation as the EGA, Haggar is joined at Zentiva by Ewan Livesey and Anant Atal (see front cover).

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COVER / Industry Veteran Haggar To Lead Prive Equity-Backed Zentiva From Next Month

4 European Council Brings SPC Manufacturing Waiver A Step Closer

6 Pfizer Axes Staff And Five Pre-Clinical Biosimilars To Fund Late-Stage Innovative Programs

7 Alvotech Advances Partnerships To Take Pipeline Global

9 Belgium Unveils Incentives For Biosimilar Adalimumab And Etanercept

9 Amneal Eyes Generic Injectables Deals, While Competition Bites Sooner Than Anticipated

12 First Sabril Rival Sees FDA Deliver On Prioritizing Competition

12 Cipla Partners With Bio-Thera For Bevacizumab In Select Emerging Markets

13 Amerigen’s Attempt To Force Fesoterodine Entry Fails

14 Court Clears Teva After At-Risk Budesonide Entry

14 Sandoz’ Hexal Avoids German Fulvestrant Use Patent

15 Switching Studies Show Safety Of Celltrion’s Infliximab Biosimilar In IBD

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P E O P L E

independent company (Also see “Zentiva sets strategy as it starts out alone” - Generics Bulletin, 5 Oct, 2018.).

Employing 2,500 people across Europe, Zentiva’s operations include a manufactur-ing facility in Prague, as well as a produc-tion site in Bucharest, Romania.

INSUD NAMES AN INTERIM CHIEF AHEAD OF HAGGAR DEPARTURE

Responding to Generics Bulletin enqui-ries, Haggar’s current employer, Insud Pharma, revealed that group chairman Leandro Sigman would assume the chief

executive officer role on an interim basis following Haggar’s departure. “We do not have any new CEO appointed,” Insud said.

Haggar pointed out that the Spanish

group had enjoyed double-digit growth over the last two years, including 14% in 2018; had doubled its investment in research and development; had “break-through innovations in the final stages of regulatory approval;” and had “substan-tially increased its capacity.”

Insud’s three subsidiary businesses in-clude biosimilars player mAbxience, which in May last year signed a licensing and sup-ply agreement in the US with Amneal for mAbxience’s Avastin (bevacizumab) bio-similar candidate.

Published online 17 January 2019

CONTINUED FROM PAGE 1 “The Zentiva opportunity

is really compelling –

a pan-European

generics player with

a strong footprint in

all market archetypes”

European Council Brings SPC Manufacturing Waiver A Step CloserDAVID WALLACE [email protected] IAN SCHOFIELD [email protected]

A mandate for negotiations with the European Parliament on a draft Reg-ulation outlining a waiver to allow

manufacturing during the term of supple-mentary protection certificates (SPCs) has been approved by the European Council.

The move brings the long-awaited SPC manufacturing waiver a step closer to frui-tion, although it remains uncertain wheth-er key elements of the proposed Regula-tion desired by the off-patent industry will be included in the draft document – including a provision allowing firms to manufacture for stockpiling for ‘day one’ launch within the European Union (EU).

CURRENT FRAMEWORK PRODUCES UNINTENDED CONSEQUENCES

Noting that “there has been huge growth in the manufacture of generics and especially of biosimilars” since the adoption in 1992 of the predecessor to the current SPC Regula-tion 469/2009, the Council’s mandate ob-serves that this has particularly been the case for countries outside the EU “where protection does not exist or has expired”.

The absence of any manufacturing ex-ception in the SPC Regulation “has had the unintended consequence of prevent-ing makers of generics and biosimilars established in the EU from making in the

EU, even for the exclusive purpose of ex-porting to third country markets in which protection does not exist”, it points out.

“A further unintended consequence is that the protection conferred by the certif-icate makes it more difficult for those mak-ers to enter the EU market immediately after expiry of the certificate,” the mandate adds, “given that they are not in a position to build up production capacity until the protection provided by the certificate has lapsed, by contrast with makers in third countries where protection does not exist.”

“This puts makers of generics and bio-similars established in the EU at a signifi-cant competitive disadvantage,” it attests, suggesting that “without any intervention,

the viability of makers of generics and bio-similars established in the EU could be un-der threat, with consequences for the EU’s pharmaceutical industrial base as a whole”.

Insisting that the waiver “does not go be-yond what is necessary and appropriate”, the Council warns that without such a mea-sure the EU “would risk substantially weak-ening its position as a hub for pharmaceuti-cal development and manufacturing”.

European off-patent industry associa-tion Medicines for Europe has long ad-vanced similar arguments in support of the SPC waiver.

However, while the Council says the draft regulation is intended to help generics and biosimilars manufacturers “in ‘day one’ EU


R E G U L AT I O N

markets, by building up production capacity”, the published man-date does not go so far as to include specific provisions relating to manufacturing for stockpiling for ‘day one’ launch within the EU, which has been a key component of the waiver desired by the off-patent industry. (Also see “SPC waiver may be altered on stockpiling and disclosure” - Generics Bulletin, 28 Sep, 2018.)

EXCLUSIVELY FOR EXPORT PURPOSESTo “create a level playing field” between EU manufacturers and those in third countries, the mandate sets out, “it is appropriate to restrict the protection conferred by a certificate so as to allow making for the exclusive purpose of export to third countries, and any related acts in the EU strictly necessary for making or for the actual export itself”.

“By limiting the scope of the exception to making for the purpose of export,” the document states, “the exception introduced by this Regulation should not conflict with the normal exploitation of the product … in the member state where the certificate is in force”.

However, later in the document the Council says the Europe-an Commission should carry out an evaluation of the draft SPC waiver Regulation that should take into account “the ability of generics and especially biosimilars to enter markets in the EU as soon as possible after a certificate lapses”.

“In particular, this evaluation should review the effectiveness of the exception in the light of the aim to restore a global level playing field for generic and biosimilar firms in the EU, and a swifter entry of generic and especially biosimilar medicines onto the market after a certificate lapses.”

SAFEGUARDS, NOTIFICATION AND DATE OF EFFECTSafeguards should accompany the exception “in order to in-crease transparency”, especially to reduce the risk of “illicit diver-sion” into EU markets during the SPC term, the Council recom-mends. To this end, a specific ‘EU Export’ logo is envisaged to be displayed on outer packaging.

Information obligations on manufacturers should include no-tifying the authority that granted the SPC in the member state or states where the manufacturing is to take place, ahead of any activity beginning. “In the interests of transparency, the author-ity should be required to publish, as soon as possible, the infor-mation it receives,” the mandate directs.

Turning to the date on which the Regulation should take ef-fect, the Council’s mandate says that “to safeguard the rights of certificate holders”, the waiver should not apply to SPCs that have already entered into effect on the date the Regulation takes effect, and should apply to any SPCs that are applied for on or after the day of the entry into force of this Regulation.

But for those SPCs that fall in the middle – those that were ap-plied for before the Regulation takes effect, but which are not yet in force by that date – the Council says it is “justified to bring [these] within the scope of the Regulation, over a certain period of time”. This should be the case “irrespective of whether or not that certifi-cate has been granted before the entry into force of the Regulation”.

“Therefore, the exception should apply, as from 1 July 2022, to a certificate that enters into effect as from that entry into force. This ‘certain period of time’ for each individual certificate that en-ters into effect after that entry into force should ensure that the

exception is applied, on a progressive basis, to such a certificate, depending on its date of entry into effect and its duration.”

This, the Council says, will allow the holder of an SPC that is not yet in effect “a reasonable period of transition to adapt to the changed legal context” while at the same time allowing generics and biosimilars manufacturers to benefit from the waiver “with-out excessive delay”.

The Council’s mandate was met with a generally positive re-sponse from Medicines for Europe.

“Medicines for Europe appreciates the agreement reached today in the Council on the SPC manufacturing waiver, which shows the political will to move the negotiations forward,” the association told Generics Bulletin.

“There is positive momentum in the Council and in the Euro-pean Parliament on the SPC manufacturing waiver. Both institu-tions seem committed to reaching a successful conclusion under this legislature and are addressing the key issues point by point.”

On the topic of ‘day one’ launches, Medicines for Europe said there was a “clear expectation from the European Parliament” to follow the opinions of the European Parliament health committee, ENVI, and the Parliament’s international trade committee, INTA.

ENVI had late last year provided an official opinion supporting the adoption of a ‘day one’ launch provision, which was subse-quently confirmed by INTA. (Also see “SPC Waiver Builds Momen-tum After EU Vote” - Generics Bulletin, 6 Dec, 2018.)

“We stress the importance of ‘day one’ launch to actually achieve the jobs and the public health benefits of the manufac-turing waiver as demonstrated by the Commission studies and impact assessment,” Medicines for Europe emphasized. “The ab-sence of the ‘day one’ launch would be detrimental to EU small and medium-sized enterprises (SMEs) and European patients.”

On notification, Medicines for Europe said the protection of commercially-sensitive confidential information was “now well understood by all parties, but it is important that this is clearly reflected in the actual wording of the manufacturing waiver”.

And on the date of applicability, the off-patent industry asso-ciation reflected that “while it is fundamental to keep the ambi-tions very high in the next weeks in order to actually achieve the benefits of the waiver as soon as possible, the progress achieved in the Council goes in the right direction”.

“There is positive momentum in the Council and in the European

Parliament on the SPC manufacturing waiver” – Medicines for Europe

“Implementation of the regulation will be at the cost of high-value research and development jobs in Europe” – EFPIA



R E G U L AT I O N

However, European brand industry association EFPIA offered a more lukewarm reaction to the Council’s mandate.

“Although the draft Regulation undoubtedly sends a signal to the world that Europe is weakening its commitment to intellec-tual property (IP) incentives and innovation,” EFPIA said, “mem-ber states’ current support of the original scope of the Commis-sion’s proposal could go some way to prevent further erosion of Europe’s IP framework as a consequence of its implementation, and must be maintained.”

“The innovative pharmaceutical industry represented by EFPIA is also very concerned about the trend in reducing a realistic tran-sition period for the application of the regulation and calls on de-cision makers to consider what is at stake,” the association stated.

It urged legislators to ensure that the final text of the Regula-tion has “no stockpiling of generic and biosimilar medicines while the innovative medicine is still under SPC protection”, as well as ensuring “a timely, effective and transparent notification system”.

EFPIA also emphasized the need for effective labelling mea-

sures to prevent products manufactured under the waiver from being re-directed back to the EU or launched on EU markets be-fore SPC expiry, and called for “non-retroactive implementation”.

These requirements, EFPIA said, were “in order to ensure that Eu-rope remains a competitive and attractive investment destination for innovative healthcare despite the SPC manufacturing waiver propos-al”. Regardless, EFPIA said, implementing the Regulation would come “at the cost of high-value research and development jobs in Europe”.

With a vote in the European Parliament’s legal affairs commit-tee (JURI) scheduled for 23 January, a resultant negotiating man-date would allow trialogues with the European Commission and Council to begin. Without such a mandate, the next opportunity for the SPC waiver Regulation to move forward will be a plenary vote, which has not yet been scheduled. This article was produced in conjunction with our colleagues at Pink Sheet.


Pfizer Axes Staff And Five Pre-Clinical Biosimilars To Fund Late-Stage Innovative ProgramsDEAN RUDGE [email protected]

P fizer has shelved development of five pre-clinical biosimi-lars following a review, concluding that the research and development dollars will be better spent on the compa-

ny’s pipeline of late-stage innovative programs.The decision will impact approximately 150 jobs, a company

spokesperson told Generics Bulletin. With three marketed biosimilars and five in mid-to-late stage

development, Pfizer stressed that the strategy “does not change Pfizer’s overall commitment to biosimilars.”

The five biosimilar assets, which were not disclosed, would not have entered the market “for at least four to eight years,” Pfizer revealed.

REALLOCATING DOLLARS TO ‘BREAKTHROUGH THERAPIES’ Pointing to the “deepest and strongest pipeline we’ve seen in years,” Pfizer reasoned, “To continue the momentum and to de-liver on our bold ambition to deliver breakthrough therapies, we must shift our investment to focus on areas of greatest potential for patients, and investors.”

The funds will be reallocated, Pfizer said, to late-stage programs across the company’s “other key therapeutic areas of research. This will support our ability to better allocate resources to cutting-edge late-stage programs in disease areas where patients have only a few or no treatment options, for example rare diseases or oncology.”

PFIZER EYES UP THREE FDA APPROVALS IN 2019Pfizer’s five-strong pipeline of mid-to-late stage development biosimilars comprises biosimilars of Herceptin (trastuzumab), Rituxan/MabThera (rituximab), Humira (adalimumab), Avastin

(bevacizumab) and Neulasta (pegfilgrastim).At the back end of last year, Pfizer was backed to receive a Eu-

ropean Union- (EU-) wide marketing authorization approval for the firm’s Avastin biosimilar, at the same time as it shelved one of its two Humira biosimilar applications (Also see “Pfizer Receives CHMP Backing On EU Bevacizumab And Withdraws Skinny Label Adalimumab UPDATED” - Generics Bulletin, 14 Dec, 2018.).

In the US, Pfizer this year faces goal dates for US Food and Drug Administration (FDA) decisions on its PF-05280014 trastuzumab biosimilar in the first quarter; its PF-06439535 bevacizumab biosimilar in the second quarter; and its PF-05280586 rituximab biosimilar in the third quarter (Also see “Pfizer looks forward to oncology potential” - Generics Bulletin, 2 Nov, 2018.).

Through its acquisition of Hospira in September 2015, Pfizer has amassed a marketed portfolio of biosimilars including:

• Inflectra/Remsima (infliximab) in the US and certain interna-tional markets, which it licenses from Celltrion;

• Nivestim/Nivestym (filgrastim) in certain European, Asian and Africa/Middle Eastern markets and in the US;

• and Retacrit (epoetin alfa/zeta) in the US and certain Euro-pean and Africa/Middle Eastern markets.

Pfizer, in December 2017, received FDA approval for its own infliximab biosimilar, Ixifi (infliximab-qbtx), but decided against commercializing it.

“We believe in the value of biosimilars for patients, for the health-care system, as well as for our investors,” Pfizer underlined.



B U S I N E S S S T R AT E G Y

Alvotech Advances Partnerships To Take Pipeline GlobalAIDAN FRY [email protected]

P ure-play biosimilars developer Alvo-tech intends within the next seven months to finalise sales, marketing

and distribution alliances with a few stra-tegic parents to commercialize the pipe-line of seven monoclonal antibody (mAb) biosimilars that the company plans to bring to market from 2020.

In an exclusive interview, Alvotech’s vice-president of business development Anil Okay – who recently moved over from sis-ter company Alvogen to assume responsi-bility for global out-licensing of Alvotech’s biosimilars pipeline – explained that the company intended to use a select roster of “perhaps five or six” strategic regional partners to market its pipeline of seven bi-osimilar mAbs. This would ensure that the alliance was a high priority for both parties.

That pipeline comprises biosimilar ver-sions of:

• AbbVie’s Humira 100mg (adalimumab)• Janssen’s Stelara (ustekinumab)• Janssen’s Simponi (golimumab)• Amgen’s Xgeva/Prolia (denosumab)• Regeneron’s Eylea (aflibercept)• Genentech’s Perjeta (pertezumab)• Takeda’s Entyvio (vedolizumab)Revealing that negotiations were al-

ready underway with potential partners for key territories, including the US and Europe, former Helm executive Okay ex-plained that Alvotech was looking to work with companies that had a proven track record and capabilities in key commer-cial channels in each region. This, he said, could range from expertise in tender-driv-en markets through to brand-building for detailing to physicians, including experi-ence in retail markets where relevant. Alliances would be formed for the entire mAb portfolio, he stated, adding that the ability to capitalise on and promote the advantages of the innovative auto-injec-tor device that Alvotech had developed with a Swiss specialist was also vital.

This type of partnering model would, he argued, give Alvotech a real competitive edge to develop multiple number of appro-priate biosimilars, supported by the early

commitment of its alliance partners.Okay told Generics Bulletin that Alvo-

tech expected in the near future to have deals in place for the world’s three largest pharma markets – the US, Japan and Chi-na. Deals for the latter two are already in place. Having at the end of September last year formed a US$200 million joint ven-ture with China’s Changchun High & New Technology Industries Group (CCHN) in a deal that includes not only commercial rights but also building a jointly-owned facility in China (Also see “Alvotech teams up with China’s Changchun” - Generics Bul-letin, 5 Oct, 2018.), Alvotech late last year handed Japanese commercial rights to Fuji Pharma (Also see “Alvotech hands Fuji rights to Japan lines” - Generics Bulletin, 23 Nov, 2018.). A few weeks later, Fuji invested US$50 million in return for a minority 4.2% stake in the biosimilars developer (Also see “Fuji Pharma Invests US$50 Million In Alvo-tech” - Generics Bulletin, 18 Dec, 2018.).

“We are not interested in cherry-picking, nor in creating direct competition for our partners in their home markets we want to strike comprehensive, long-term deals for our entire pipeline with the selected top-tier partners,” Okay explained.

While talks were ongoing with multina-tional companies interested in acquiring rights to Alvotech’s mAbs for both North America, Canada and Europe, he said the developer was currently evaluating all op-tions. These, he added, could include draw-ing on sister company Alvogen’s expertise garnered in Central and Eastern Europe (CEE) by promoting Pfizer unit Hospira’s roster of biosimilars such as Inflectra (inflix-imab). Capitalising on Alvogen’s expanding presence in the Asia-Pacific region remained a viable option, he said, identifying Australia as a promising market for biosimilars.

TURKEY AND MENA ALLIANCES ARE LINED UP

Okay stressed that Alvotech was not overlooking emerging markets’ potential as it discussed partnership deals. Alli-ances for both Turkey and the Middle East

and North Africa (MENA) were in place and scheduled to be announced within the next few weeks, he disclosed. Nego-tiations over commercial rights in Latin America were also underway, he said. “We have the right market access, pricing and intellectual-property plans to maximize the value via early entries in emerging markets,” he added.

With both Alvotech’s adalimumab 100mg and ustekinumab biosimilar candidates now hitting in the clinical phase of devel-opment in 2019, Okay said potential com-mercial partners were increasingly keen to strike a deal. However, finding the right partners was more important than rushing into alliances, he stressed.

Alvotech was exceptional, Okay con-tended, in having self-financed clinical programs for all of its mAb pipeline with-

“We are not interested in cherry-picking,

nor in creating direct competition for our

partners in their home markets we want to strike

comprehensive, long-term deals for our entire pipeline with the selected

top-tier partners”




out third-party support. The developer was also one of very few to have publicly committed to performing the studies nec-essary for obtaining interchangeability designations in the US that would permit substitution at pharmacy level and confer at least one year of exclusivity precluding other companies for securing a similar designation for a similar product.

Interchangeability designations, Alvo-tech believes, could help to substantially improve the currently lacklustre biosimi-lar uptake rates seen in the US. This, Okay argued, would be particularly important given that the company’s pipeline in-cluded four chronic-use treatments for autoimmune diseases for which change of therapy was typically infrequent.

Discussing the adalimumab 100mg/ml opportunity, Okay observed that AbbVie’s higher-strength reformulation of Humira had been welcomed by patients and pre-scribers for reducing injection pain and bringing better patient compliance. Howev-er, to date, it seemed to have attracted little attention from other biosimilar developers.

Intellectual property, regulatory affairs and clinical development are run out of

Alvotech’s office in Zürich, Switzerland, to capitalise on the expertise available local-ly. Alvotech uses Germany as the research and development (R&D) center of excel-lence within its best-in-class centers; the protein characterization and analysis spe-cialist GlycoThera that Alvotech acquired by 2017, located in Hanover, Germany and its cell-line development center located in Julich, Germany, provide “an important competitive edge to the company by hav-ing access to best possibly available know-how in the industry”.

Clinical and commercial manufactur-ing is conducted at Alvotech’s newly con-structed 13,000 sq m facility in Reykjavik, Iceland, that recently obtained good manufacturing practice (GMP) clearance. The plant houses both Chinese hamster ovary (CHO) and SP2/0 mouse myeloma cell lines, as well as perfusion technol-ogy, while it employs disposable single-use bioreactors for both flexibility and cost-competitiveness.

Okay stressed that “as of today, we built the newest facility in the biosimilar industry with the best-in-class technol-ogy platform that is up and running, we designed the facility in a way to be pre-pared for the cloudy days of an expect-ed price wars with which we all familiar from commoditized generic business”. He added that Alvotech could also scale up capacity at the site, demonstrating its long-term commitment to biosimilars.

VERTICALLY INTEGRATED MODEL CONFERS BENEFITS

Alvotech, Okay pointed out, was one of only a handful of biosimilar developers that possessed vertically integrated man-ufacturing and development capabilities, as most players had outsourced some part of the value chain from cell-line develop-

ment through to commercial fill-and-fin-ish. This fully integrated model should, he believed, provide greater supply reliability and control over cost of goods, while en-suring that Alvotech and its partners were able to launch in all available markets with full supply immediately upon market for-mation. “Outsourcing adds increased cost, supply uncertainty, quality concerns, and extended timelines, which we do not want to face here at Alvotech,” he explained.

As few patents protecting originator biologics had been filed in Iceland, Alvo-tech was able to stockpile for commercial supply ahead of intellectual-property rights expiring, Okay noted, adding that this was likely to confer an advantage of an earlier market entry. This, along with the recent good manufacturing practice (GMP) approval, was attracting several parties interested in using the site for contract manufacturing ahead of Alvo-tech’s pipeline starting to reach the mar-ket from next year.

With the biosimilars commercial land-scape still evolving – and several parties, both pure-play biosimilar developers and multinational pharma entities, cull-ing development programs – Alvotech feels it is well placed at the very right time to prosper, regardless of the distri-bution channel or competitive dynamic. “Portfolio depth will play the critical role in being successful in the biosimilars business; therefore, with our strategic al-liances in place, we are going to create a biosimilar portfolio engine”. And even if pricing developed towards trends in the commoditized generics arena, the com-pany was committed to competing. “We are prepared for any market scenario,” Okay insisted.


“We designed the facility in a way to be prepared

for the cloudy days of an expected price wars with

which we all familiar from commoditized

generic business”

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R E G U L AT I O N

Belgium Unveils Incentives For Biosimilar Adalimumab And EtanerceptDAVID WALLACE [email protected]

A pilot scheme to encourage uptake of anti-tumor necro-sis factor (anti-TNF) biosimilars adalimumab and etaner-cept outside of hospitals through financial incentives for

prescribing doctors has been launched in Belgium.“This is a pilot case, but is historical as this is the first time ever

that a financial reward has been attributed,” Belgian off-patent industry association Medaxes told Generics Bulletin.

Following negotiations involving local doctors associations and health insurer INAMI that concluded in December, it was agreed that INAMI would for the whole of 2019 monitor pre-scription rates for all doctors prescribing anti-TNF biosimilars.

Doctors will be assessed on whether they pass certain thresh-olds of biosimilar prescribing, measured by defined daily dose (DDD). Milestones of 5%, 10% and 20% biosimilar prescribing within the product category – which groups both adalimumab and etanercept – will trigger annual payments ranging from €750 (US$854) to €1,500, payable in early 2020.

“During this period, a scientific study will run regarding re-sults, including switches, and the project will be evaluated peri-odically to assess next steps,” Medaxes pointed out.

The move comes after Belgian medicines agency AFMPS and

local health insurer INAMI recently launched a public informa-tion campaign to educate patients and doctors on biologics and to encourage the uptake of biosimilars.

This was accompanied by further measures to support biosim-ilar uptake, such as regular monitoring of biosimilar prescribing, a study on prescribing habits, and the appointment of a biosimi-lars ‘ambassador’. (Also see “Belgian Body Bolsters Awareness Of Biosimilars” - Generics Bulletin, 18 Dec, 2018.)


Amneal Eyes Generic Injectables Deals, While Competition Bites Sooner Than AnticipatedDEAN RUDGE [email protected]

Amneal Pharmaceuticals’ continued generation of “strong cash flows” means the company is “open for business” for mergers and acquisitions, in particular a deal that would

swell its burgeoning generic injectables presence, although pay-ing down debt remains a core strategy.

Management also admitted during the recent J.P. Morgan Healthcare Conference held in San Francisco, California, that, in the fourth quarter of 2018, Amneal had been surprised by generic competition to some of its top-selling generic products “earlier than expected;” but insisted that Amneal “had been able to push through despite those headwinds.”

GENERIC AND BRANDED INJECTABLE DEALS UNDER CONSIDERATION

Addressing delegates to the conference, president and chief execu-tive officer Robert Stewart revealed, “It would be nice maybe to have a little bit of a bigger injectable portfolio. We’re about 30 products in market, as well as future launches [planned] here. And we have a pathway to be able to double that within the next several years.

“But if we have the ability to accelerate our growth on the in-jectable side through M&A on the generics side, that certainly would be something that we would consider,” Stewart said.

“And it’s not just generic injectables either,” he admitted. “It’s also branded injectable that could be of interest, because [the company] can really leverage our institutional salesforce as well as our infrastructure that we have there.”

SCALE DOES NOT ALWAYS DRIVE VALUE, STEWART SAYS Capturing synergies more quickly than anticipated through the Am-neal-Impax merger had put Amneal in the cash position necessary to move on such deals, Stewart said, “as well as the way we have man-aged the supply chain;” including through closing the former Impax manufacturing facility in Hayward, California, ahead of schedule.

Stewart underlined that Amneal had “just about all the capa-bility that we need” for its generics business. “And,” he insisted, “I don’t necessarily think that scale always drives value.”

Executive chairman Paul Bisaro added that on top of chasing deals to bolster Amneal’s pipeline and portfolio, the firm would




also continue looking at deals through which the patient would serve directly as the customer.

“I think we all know the generics space is suffering from an inability to get to patients and we need to find a way to do that,” Bisaro said. “We’ll continue to focus on that area, whether it’s di-rect distribution, or whether it’s a cash-pay business that gives us the ability to leverage our generics franchise.”

Per data presented by the company to investors, 15% of Am-neal’s pipeline of filed applications are for injectables products; for in-development products, the number is higher, at 25%. Ac-cording to Stewart, Amneal has “one of the best pipelines in the industry with over 220 generic products either in development or filed with the US Food and Drug Administration (FDA).”

“Long-acting injectables is a core focus of ours,” Stewart said. “And so, as we get closer to providing a little bit more detail around the pipeline in future forecasts, we’ll [provide] a little more color [on] what’s in the pipeline and what’s filed. But you can ex-pect that Amneal is very, very focused on long-acting injectables.”

Amneal on 14 January celebrated FDA approval for its first trans-dermal product, its generic of Novartis’ Exelon (rivastigmine) trans-dermal patch, demonstrating, according to Stewart, the firm’s “com-mitment to develop and bring to market complex generic products.”

COMPETITION BITES FOR AMNEAL IN Q4 2018 Reflecting on the onrush of generic competition that had ar-rived in the final quarter of last year, Stewart joked, “I was afraid to pick up the phone at one point.”

He ticked off as receiving generic competition “all within a week of each other” Amneal’s three highest-selling products by value in the first nine months of 2018: Yuvafem (estradiol), diclofenac sodium gel and aspirin/dipyridamole extended-release capsules.

With sales of US$106 million, US$78.6 million and US$67.7 million respectively, the products accounted for 9%, 7% and 6% of Amneal’s nine-month turnover that leapt by 57.4% to US$1.17 billion, following the merger of Amneal and Impax on 7 May 2018.

“Then we saw an Albenza (albendazole) generic too, all within 10 days of each other,” Stewart continued. But he maintained, “These are still great products for us. They’re still generating great margins.

“Yeah, you’ll see a tick down in terms of market share week over week on many of these,” he admitted.“But you’ll still see us holding on to a significant portion of share, and we’ve been pleased with the pricing environment so far.”

Going further on pricing, Stewart said that he agreed with some of his peers, including Teva president and chief executive officer Kåre Schultz (Also see “US Pricing Pressures Have Stabilized, Insists Teva Chief” - Generics Bulletin, 9 Jan, 2019.), that Amneal was “seeing more price stability. I’m seeing a much different rela-tionship with the buying groups today than we’ve seen in years past,” he noted, “and it’s much more constructive.”

By launching up to 50 generic products in 2019, Amneal was confident that it could continue to drive value, Stewart said, building on the company’s 42 launches in 2018. More than a third of the 2018 launches were injectable, topical or liquid products, including seven injectables.

“I do think that 30 to 40 launches a year is sustainable for us,” said Stewart, “given our pipeline and the number of assets that we have in the pipeline and development.”

ALL THREE BIOSIMILAR ASSETS TO BE FILED BY Q2 2020 Amneal’s three-strong pipeline of biosimilars includes a partner-ship with Adello Biologics for Neupogen (filgrastim), which has been filed, and Neulasta (pegfilgrastim), which is to be submit-ted in the first half of 2019; as well as with mAbxience for Avastin (bevacizumab), which is to be filed in the first half of 2020.

On Neulasta, Stewart conceded that Amneal was late in filing, having originally planned a submission in the final quarter of 2018. “We’re going to continue to take a partnership approach in bio-similars and we’re going to weigh our milestone payments more towards approval success, as well as commercial success, because we’ve seen this market being slow to develop,” Stewart noted.

“And so, what we’re going to do is take a ‘fast follower’ ap-proach and try to be in the market later, as it ultimately starts opening up and delivering returns.”


“You can expect that Amneal is very, very focused on long-acting injectables.”

Amneal's Pipeline Of Filed And In DevelopmentProducts

While more than half of Amneal's submitted assets are oral solids, this figure drops to just more thana third for in development products. The firm also has a broader percentage of injectables in its

development pipeline; and more than half-a-dozen inhalation assets currently under development,compared to zero that are filed.

Submitted Products

Injectables 15.32%

Ophthalmics 4.84%

Inhalation 0.00%

Topicals 8.87%

Transdermals 4.84%

Liquid/Suspensions 9.68%

Nasal Sprays 0.81%Vaginal/Rectal 1.61%

Oral Solids 54.03%

In Development Products

Injectables 25.00%

Ophthalmics 13.54%

Inhalation 7.29%Topicals 7.29%

Transdermals 4.17%

Liquid/Suspensions 5.21%Nasal Sprays 3.13%

Vaginal/Rectal 0.00%

Oral Solids 34.38%

Breakdown by dosage form of Amneal's pipeline of 124 filed products and 96 in development products (Source - AmnealPharmaceuticals)

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G E N E R I C S

First Sabril Rival Sees FDA Deliver On Prioritizing CompetitionGRACE MONTGOMERY [email protected]

T eva has been granted approval by the US Food and Drug Administra-tion (FDA) for the first US generic

rival to Lundbeck’s Sabril (vigabatrin) 500mg tablets, as the agency reiterates its focus on “prioritizing the approval of generics to compete with medicines that face little or no competition”.

FDA Commissioner Scott Gottlieb stressed that the “availability of high-quality generic alternatives of critically important medicines, once the period of patent pro-tection or exclusivity has ended on the brand drug, helps advance access and saves consumers billions of dollars each year”.

He pointed out that in 2018, the agen-cy included vigabatrin tablets on a list of off-patent, off-exclusivity branded drugs without approved generics, to “clarify that there were no patents or exclusivities that should impede its approval”.

Noting that the list was part of efforts the FDA began in 2017, Gottlieb said that the agency would “continue to refine and update [it] periodically to ensure continued transparency around drug categories where increased competition has the potential to provide significant benefit to patients”. He maintained that the approval of Teva’s gener-

ic vigabatrin “demonstrates that there is an open pathway” to approving such products.

Teva’s vigabatrin tablets are FDA-ap-proved for the treatment of refractory complex partial seizures as an adjunctive therapy in patients 10 years of age and older who have responded inadequately to sev-eral alternative treatments. The Israeli firm’s generic is part of a single shared-system Risk Evaluation and Mitigation Strategy Program (REMS) with other drug products containing vigabatrin to ensure safe use of the product.

Teva is one of five companies to currently hold abbreviated new drug application (ANDA) approval for vigabatrin 500mg so-lution, on which Endo’s Par led the way. Like the tablets, the vigabatrin solution format is not covered by any unexpired patents or exclusivities listed in the FDA’s Orange Book.

FDA AIMS FOR MORE EFFICIENT GENERIC REVIEW PROCESS

“We’re especially focused on new poli-cies aimed at making the generic review process more predictable, efficient and lower cost,” Gottlieb stated, “so we can entice more generics firms to enter this space, and help facilitate more generic drug launches after generic approvals.”

“We know it’s not enough just to ap-prove a record number of generic medi-cines,” he insisted, citing data from the agency’s fiscal year ended 30 September 2018 that recorded a total of 971 final and tentative approvals granted by the FDA’s Office of Generic Drugs (OGD) dur-ing the 2017-2018 financial year (Also see “Record ANDAs don’t solve all problems” - Generics Bulletin, 19 Oct, 2018.). “We also want to see firms launch these products so that patients can benefit from their availability, and we intend to take steps to advance these goals.”

In 2018, the FDA began to publish a list of inquiries from generic drug develop-ers seeking the agency’s assistance in ob-taining samples from brand companies, noting that the originators were poten-tially blocking access to samples when the brand products were subject to limited distribution programs, including REMS. Sabril was included on this list. “The FDA has continued to emphasize that even in the case of limited distribution programs, there should be a path forward for generic drug development,” Gottlieb said.


Cipla Partners With Bio-Thera For Bevacizumab In Select Emerging MarketsGRACE MONTGOMERY [email protected]

C ipla has inked a licensing agree-ment with Bio-Thera Solutions for its BAT1706 bevacizumab bio-

similar, under which the Indian firm will have exclusive rights to distribute and sell the biosimilar of Genentech’s Avastin in “select emerging markets”.

Bio-Thera said that the partnership “will leverage Cipla’s strong local pres-ence, sales and marketing capabilities in the select emerging markets”, but spe-

cific markets were not disclosed.Bio-Thera will be responsible for “full

development, product registration with the US Food and Drug Administration (FDA) and European Medicines Agen-cy (EMA), and commercial supply of BAT1706 out of its manufacturing facili-ties in Guangzhou, China”.

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squamous non-small cell lung cancer. Bio-Thera’s biosimilar is cur-rently in a global Phase III study in patients with previously untreat-ed advanced non-squamous non-small cell lung cancer.

Bio-Thera intends to file for regulatory approval with China’s National Medical Products Administration (NMPA), the EMA and the FDA in 2020.

Umang Vohra, Cipla’s chief executive officer (CEO), said the agreement was “in keeping with Cipla’s stated intention to build a strong pipeline of biosimilars through partnerships”. “We are committed to working towards ensuring patients receive access to life-saving drugs,” he commented. “Through this partnership, Cipla will leverage its strengths in marketing to take this key on-cology biosimilar to patients in need.”

Shengfeng Li, Bio-Thera’s CEO, said the firm was “pleased to partner with Cipla to commercialize our lead biosimilar program in select emerging markets”. He described the partnership as “an important first step towards making BAT1706 available globally to help increase patient access to this important cancer thera-peutic at affordable prices”.

Bio-Thera is also currently developing BAT1406, an adali-mumab biosimilar, which in October 2018 had its biologics license application (BLA) accepted for review by the NMPA. The firm’s BAT1806 tocilizumab biosimilar is in late-stage clinical trials.


Amerigen’s Attempt To Force Fesoterodine Entry FailsAIDAN FRY [email protected]

A n attempt by Amerigen Pharmaceuticals to clear a legal route to launching a generic version of Pfizer’s Toviaz (fes-oterodine fumarate) extended-release tablets in the US has

failed. The US Court of Appeals for the Federal Circuit has upheld a 2017 inter partes review (IPR) holding that US patent 6,858,650 – which expires on 3 July 2022 – was not unpatentable as obvious.

In July 2017, the Patent Trial and Appeal Board (PTAB) within the US Patent and Trademark Office (PTO) had upheld in light of prior

art the ‘650 patent, which Pfizer licenses from UCB to protect its To-viaz urinary incontinence brand. It would not have been obvious, the PTAB determined, to modify the active compound 5-hydroxy-methyl tolterodine (5-HMT) to make the fesoterodine prodrug.

Addressing first UCB’s assertion that Amerigen lacked standing to appeal the IPR holding because a Delaware district court had previ-ously upheld the ‘650 patent in a separate suit, the Court of Appeals noted that Amerigen currently held tentative approval from the US Food and Drug Administration (FDA) for its fesoterodine fumarate 4mg and 8mg extended-release tablets.

INVALIDATING PATENT COULD OPEN PATH TO 2019 LAUNCHInvalidating the ‘650 patent would, the court pointed out, un-block Amerigen’s path to final FDA approval, potentially enabling the generic firm to launch this year, even if another company were eligible for 180-day generic market exclusivity. Several oth-er patents listed against Toviaz in the FDA’s Orange Book expire on 11 May 2019. Thus, Amerigen had “a concrete, economic inter-est” in the outcome of its appeal that conferred standing.

Turning to obviousness, the Court of Appeals noted that Amerigen was alleging that the PTAB had: misunderstood the firm’s arguments on lipophilicity; placed an excessive burden on Amerigen to show a motivation to make a 5-HMT prodrug; and failed to recognize that arriving at the claimed compounds would have been routine optimization.

Having considered expert testimony, the Court of Appeals found that “substantial evidence supports the Board’s finding that a person of ordinary skill would not have been motivated to modify 5-HMT to increase its lipophilicity”. The same skilled person would have realized that developing a prodrug would “involve trade-offs” versus the ac-tive compound, so would have lacked motivation to modify 5-HMT. And even if a skilled person would have been motivated to modify 5-HMT, Amerigen had failed to prove that person “would have made the specific modifications leading to the claimed compounds”.

Pfizer reported US Toviaz sales that slipped slightly to US$62 million in the first nine months of 2018.




I N T E L L E C T UA L P R O P E R T Y

Court Clears Teva After At-Risk Budesonide EntryAIDAN FRY [email protected]

Teva has been vindicated in choos-ing to launch ‘at risk’ last year the first US alternative to Valeant’s Uce-

ris (budesonide) ulcerative colitis treat-ment. The US Court of Appeals for the Federal Circuit has affirmed without com-ment a Delaware district court’s deter-mination from 2017 that generic tablets from both Teva’s Actavis and Alvogen did not infringe US patent 8,784,888 that ex-pires on 9 June 2020.

Actavis obtained final approval for budesonide 9mg extended-release tablets from the US Food and Drug Administration (FDA) in early July last year. This permitted parent company Teva to immediately an-nounce an ‘at risk’ launch while Valeant and partner Cosmo appealed against the Delaware court’s non-infringement ruling delivered by Judge Leonard Stark.

APPEAL DECISION REMOVED RISK OF DAMAGES

At the time of Actavis securing FDA ap-proval, Cosmo had warned that an ‘at-risk’ generic launch would “expose Teva to pay significant damages” if the Court of Appeals reversed Stark’s verdict. A panel of three Court of Appeals judges – Chief

Judge Sharon Prost and Circuit Judges Jimmie Reyna and Richard Taranto – on 14 January affirmed Stark’s verdict per cu-riam without further comment, removing any risk of Teva having to pay damages.

Citing IQVIA data for the 12 months ended May 2018, the Israeli firm had said upon launching that Uceris had an-nual US sales of US$196 million. Valeant – which last year took a US$263 million impairment charge due to generic com-petition to the glucocorticosteroid – put its Uceris tablet sales at US$134 million in calendar 2017 and US$70 million in the first half of 2018.

The ‘888 patent was one of 10 patents to which Teva made Paragraph IV certifica-tions of invalidity or non-infringement in its budesonide abbreviated new drug applica-tion (ANDA). Seven of those patents share the same 9 June 2020 expiry date, while the other three expire on 7 September 2031.

In its approval letter, the FDA noted that Valeant and Cosmo had sued Acta-vis over five 2020 patents and one 2031 patent within the 45-day period that trig-gered a 30-month stay on final approval. In November 2017, the ‘888 patent and US patent 8,293,273 were found not to have

been infringed by the Delaware court, which also dismissed cases over the other four patents. A dispute over another 2031 patent, 9,132,093, was also dismissed.

Acknowledging that Actavis was in principle eligible for 180-day generic market exclusivity as a first ANDA appli-cant to make a Paragraph IV certification to Uceris patents, the FDA observed that the company had failed to obtain tenta-tive ANDA approval within 30 months of filing, and thus may have forfeited ex-clusivity. However, the agency declined to make a formal decision on exclusiv-ity until another paragraph IV filer was set for approval. To date, Actavis holds the only ANDA approval for budesonide 9mg extended-release tablets.


Sandoz’ Hexal Avoids German Fulvestrant Use PatentAIDAN FRY [email protected]

A generic rival to AstraZeneca’s Faslodex (fulvestrant) oncology drug that is marketed in Germa-

ny by Sandoz’ Hexal affiliate does not infringe the local version of European method-of-use patent EP1,272,195, a Düsseldorf upper regional court has de-cided. The appeals court’s decision up-holds a Düsseldorf lower court’s findings from July last year.

The ‘195 patent covers the use of ful-vestrant to make a medicine for treating patients with breast cancer who have pre-viously been treated unsuccessfully with tamoxifen and an aromatase inhibitor such as anastrozole and letrozole. Bifur-

cated invalidity proceedings against the patent are underway before Germany’s federal patent court.

FINDING LAST YEAR WAS IN SANDOZ’ FAVOR

AstraZeneca alleged that Hexal’s generic fulvestrant 250ml solution for injection, which was first listed in Germany’s Lauer-Taxe price list towards the end of 2015, infringed the ‘195 patent. The originator initially succeeded in obtaining a tempo-rary injunction against Hexal’s generic, but that was subsequently overturned, and the Düsseldorf lower court last year found in the Sandoz affiliate’s favor.

In asserting infringement on appeal, AstraZeneca relied on an evaluation of a register of 444 patients with breast cancer which suggested that 45.7% of patients had undergone unsuccessful treatment with an aromatase inhibitor and tamoxi-fen before being prescribed fulvestrant.

“If the generics company is aware of the prescribing practices that benefit it, or at least should have been aware, and ex-ploits such practices through deliveries to wholesalers, it is appropriate to hold the generics manufacturer accountable under patent law.”

However, the Düsseldorf appeals panel pointed out that Hexal’s product


B I O S I M I L A R S

was “not directed to the patented us-age” and the generics labelling made “no mention at all” of treatment failure with an aromatase inhibitor. For the plaintiff to prove infringement, it would have demonstrate “sufficient, not merely isolated” usage of the generic within the scope of the patent and that the generic firm was aware of such usage or was act-ing in bad faith.

“If the generics company is aware of the prescribing practices that benefit it, or at least should have been aware, and exploits such practices through deliveries to wholesalers, it is appropriate to hold the generics manufacturer accountable under patent law,” the Düsseldorf upper regional court stated.

Highlighting the “central relevance” of a drug’s approved labelling to its pre-scription and usage, the court said it was crucial to decide whether the generic was “manifestly arranged” to fulfil the patented use or whether the generic, at the time of trial, was not typically pre-scribed for the patented use.

INSUFFICIENT EVIDENCE TO SHOW INFRINGING USE

“The plaintiff’s evidence does not show that the defendant’s disputed product is or has been used to a sufficient extent due to actual prescribing practice,” the appeals panel concluded, pointing to registry data that showed the use of ful-vestrant after palliative treatment with tamoxifen and an aromatase inhibitor falling from 6.9% in the 2007-2009 time-frame to no recorded use in 2015-2016. Thus, there had at the time of an oral hearing on 9 January this year not been “a single case of a fulvestrant prescription within the scope of the patent within the past four years”.

Hexal’s German victory on fulvestrant comes shortly after the Court of Appeal of the Hague in the Netherlands overturned a district court’s finding from earlier this year that the local part of two European formulation patents protecting Faslodex - EP1,250,138 and EP2,266,573 - were in-valid for lack of inventive step over prior-art references (Also see “Sandoz Stutters On Dutch Fulvestrant “ - Generics Bulletin, 11 Dec, 2018.).


Switching Studies Show Safety Of Celltrion’s Infliximab Biosimilar In IBDGRACE MONTGOMERY [email protected]

D ata indicating the safety of Celltri-on’s CT-P13 infliximab biosimilar has been published this month

in two separate studies. One explores switching pediatric patients with inflam-matory bowel disease (IBD) from Janssen’s Remicade to the South Korean biosimilar developer’s infliximab, while the second focuses on patients with IBD changing from CT-P13 to the originator drug.

Firstly, a study published in the Thera-peutic Drug Monitoring journal evaluated long-term infliximab trough levels, immu-nogenicity and remission rates in children with IBD who switched from the reference brand to Celltrion’s CT-P13 biosimilar.

Noting that “rising evidence demon-strates that there are no differences in effi-cacy and safety” between the infliximab ref-erence drug and the CT-P13 biosimilar in the treatment of IBD, the study observed that “most data are derived from adult patients and data on pharmacokinetics are limited”.

The single-center study included 42 children – 26 of whom had Crohn’s disease and the remaining 16 ulcerative colitis. All children receiving maintenance infliximab therapy were switched from the originator drug to CT-P13. “Demographics, disease activity indices and infliximab drug levels were collected from six months before till six months after switching to CT-P13,” the study noted.

Results found that after switching, “no significant changes in infliximab trough levels occurred” and the “proportion of pa-tients in clinical and/or biological remission did not significantly change”. “Antibodies to infliximab appeared in one patient after switching,” the report discovered.

“No significant changes were observed in C-reactive protein, erythrocyte sedimen-tation rate, albumin, weight and body mass index after the switch,” the study contin-ued. “Safety profile was also comparable.”

In conclusion, the report maintained that pediatric IBD patients on the inf-liximab originator “can be successfully

switched during maintenance to biosimi-lar CT-P13 without affecting efficacy, phar-macokinetics, immunogenicity or safety”.

REVERSE SWITCHING IS SAFEA second study, published in the Clinical Gastroenterology and Hepatology journal, aimed to evaluate the effects of a reverse switch – from a biosimilar to Remicade – in a “real-life cohort”. “There is evidence that it is safe and effective for patients with IBD to switch from maintenance therapy with an original infliximab drug to a biosimilar,” the study stated, “but little is known about outcomes of reverse switches and/or mul-tiple switches.”

This involved an observational study of 174 patients with IBD – 136 with Crohn’s disease and 38 with ulcerative colitis – who received maintenance therapy with the biosimilar in Hungary. In September 2017, patients were switched from CT-P13 to Remicade, due to reimbursement policies.

Noting that 8% of patients – 14 – had been previously exposed to the origina-tor Remicade, the study collected clinical and biochemical information from pa-tients at the time of the switch – or ‘base-line’ – and 16 and 24 weeks thereafter.

“There was no significant difference in the proportion of patients in clinical remis-sion at week 8 before the switch, at base-line, at week 16 or at week 24,” the report found. “We did not find significant differ-ences in prevalence of antidrug antibody at baseline compared with week 24.” Four infusion reactions occurred, until week 24 of follow-up. “There was no difference in outcomes or trough or antidrug antibody levels between patients with or without previous exposure to Remicade.”

“No significant changes were observed in remission, trough levels, or antidrug an-tibodies in patients switched from the bio-similar to Remicade,” the study concluded. “No new safety signals were detected.”



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