Therapeutic focus – Anti-thrombotic market in need of more deals

Analysis

Novartis’ decision to license phase II anti-clotting agent elinogrel from private US biotech Portola Pharmaceuticals for $75m upfront today is both intriguing and surprising when considering that the current gold standard anti-thrombotic agent, Plavix, will be off-patent in two years and the recent tortuous path to regulatory approval for Eli Lilly’s Effient.

Although the full terms of the deal were not disclosed, the upfront fee suggests this is the biggest product deal in this field since Pfizer licensed apixaban, whilst in phase III trials, from Bristol-Myers Squibb for $250m upfront in April 2007. The Novartis-Portola deal also bucks a recent trend for rapidly declining deals for anti-thrombotic agents, with just three partnerships signed last year in comparison to 17 deals in 2004 (see tables below).

Plavix patent expiry overhang

According to forecast data from EvaluatePharma, the anti-thrombotic agent market was worth $19.1bn last year and is set to decline marginally by 2014 with revenues of $18.8bn.

Although potential blockbusters, such as Bayer/Johnson & Johnson’s Xarelto and Eli Lilly/Daiichi Sankyo’s Effient, are poised to enter the market this year, patent expiries for the sector’s two biggest-selling products, Plavix in 2011 and Lovenox in 2012, are expected to put a significant brake on overall revenue growth.
 

Anti-Thrombotic Agent Market: 2008 - 2014 WW annual sales ($m)
Rank Product Generic Name Pharmacological Class Company (s) Phase Patent Expiry 2008 2014 CAGR (08 - 14)
1 Plavix clopidogrel Platelet ADP antagonist Sanofi-Aventis + Bristol-Myers Squibb Marketed  Nov 2011  9,431  2,477   (20%)
2 Lovenox/Clexane enoxaparin Heparin, low molecular weight Sanofi-Aventis Marketed  Feb 2012  4,007  2,267   (9%)
3 Pradaxa dabigatran Thrombin inhibitor Boehringer Ingelheim Marketed  -  88  2,188  71%
4 Xarelto rivaroxaban Factor Xa inhibitor Johnson & Johnson + Bayer AG Filed  -  10  1,823  n/m
5 Effient prasugrel Platelet ADP antagonist Eli Lilly + Daiichi Sankyo Filed  -  10  1,416  n/m
6 SCH 530348 - Thrombin inhibitor Schering-Plough Phase III  -  -  871  n/a
7 AZD6140 ticagrelor P2Y12 antagonist AstraZeneca Phase III  -  -  646  n/a
8 Apixaban apixaban Factor Xa inhibitor Bristol-Myers Squibb Phase III  Feb 2023  -  615  n/a
9 Pletal/Pletaal cilostazol Phosphodiesterase III inhibitor Otsuka Pharmaceutical Marketed  Jan 2004  416  585  6%
10 Activase / Actilyse alteplase Plasminogen activator Boehringer Ingelheim + Genentech Marketed  -  529  569  1%
Other products  4,561  5,305  
Total Anti-Thrombotic Agent Market 19,051 18,762  (0%)

Platelet aggregation inhibitors

Plavix, Effient and elinogrel are all platelet aggregation inhibitors, a class of drug that accounted for 65% of the total anti-thrombotic market last year. However, the patent expiry for Plavix, the industry’s second biggest product in 2008 with sales of $9.43bn behind Lipitor at $12.4bn, means that revenues for this class of drug are forecast to decline 7% annually to $8.1bn by 2014.

Platelet Aggregation Inhibitor Market: 2008 - 2014 WW annual sales ($m)
Rank Product Generic Name Pharmacological Class Company (s) Phase Patent Expiry 2008 2014 CAGR (08 - 14)
1 Plavix clopidogrel Platelet ADP antagonist Sanofi-Aventis + Bristol-Myers Squibb Marketed Nov 2011 9,431 2,477 (20%)
2 Effient prasugrel Platelet ADP antagonist Eli Lilly + Daiichi Sankyo Filed - 10 1,416 n/m
3 AZD6140 ticagrelor P2Y12 antagonist AstraZeneca Phase III - - 646 n/a
4 Pletal/Pletaal cilostazol Phosphodiesterase III inhibitor Otsuka Pharmaceutical Marketed Jan 2004 416 585 6%
5 Aggrenox/Asasantin dipyridamole & aspirin Phosphodiesterase inhibitor & cyclo-oxygenase inhibitor Boehringer Ingelheim Marketed Jan 2017 448 547 3%
6 CardioAspirin aspirin Cyclo-oxygenase inhibitor Bayer AG Marketed - 378 462 3%
7 Opalmon limaprost Prostaglandin E1 Ono Pharmaceutical Marketed - 387 451 3%
8 Cangrelor cangrelor P2Y12 antagonist The Medicines Company Phase III Feb 2014 - 273 n/a
9 Integrilin eptifibatide GP IIb & IIIa antagonist Schering-Plough Marketed Nov 2014 314 265 (3%)
10 ReoPro abciximab Anti-GP IIb & anti-GP IIIa MAb Eli Lilly Marketed Dec 2015 256 199 (4%)
Other products 791 756  
Total Platelet Aggregation Inhibitor Market 12,431 8,076 (7%)

Declining deals

Since 2000, 96 product deals have been signed across all anti-thrombotic agents, the bulk of which occurred between 2003 and 2006. However, the dominance in the market of just a handful of drugs which in the main are able to meet the medical need, is likely to have turned companies away to some extent from developing and seeking to license new anti-coagulant products, hence the recent decline in product deals.

Product Deals for Anti-Thrombotic Agents
Deal Date Deal Count
2008 3
2007 8
2006 11
2005 14
2004 17
2003 10
2002 11
2001 14
2000 8
Total 96

With respect to platelet aggregation inhibitors, the deal landscape is even more barren, with just six partnerships within the last five years, hence the slight surprise in Novartis’ move for Portola’s drug.
 

Product deals for platelet aggregation inhibitors: last 5 years
Deal Date Company Deal Type Product Deal Partner/ Product Source Status on Deal Current Phase
Aug-07 Nile Therapeutics In-licensed 2NTX-99 Dr. Cesare Casagrande Pre-clinical Pre-clinical
Jan-07 Takeda Out-licensed technology PR-15 Trigen Phase I Phase I
Dec-06 AstraZeneca In-licensed Cerylid kinase inhibitor Cerylid Biosciences Pre-clinical Pre-clinical
Oct-06 MediciNova In-licensed MN-447 Meiji Seika Kaisha Pre-clinical Pre-clinical
Feb-05 Pfizer In-licensed ADP receptor antagonist program Schering AG Research project Abandoned - Research project
Jan-04 ThromboGenics In-licensed Anti-VPAC Katholieke Universiteit Leuven Research project Pre-clinical

In addition, elinogrel has only successfully completed one phase IIa trial to date, with the results of an ongoing phase IIb trial due by the end of 2009 likely to provide the first real test of the drug’s safety and efficacy.

The phase IIb trial will enrol 800 patients and will test both intravenous and oral forms of the drug, and importantly is designed as a head-to-head trial with Plavix. Given that Plavix will be available generically by the time elinogrel reaches the market, it is clearly massively important that comparative efficacy and safety data is well defined in order to gain regulatory approval and then a decent share of the market.

Critical success factors

Portola believes that elinogrel’s commercial success will be based on the drug’s instant onset of action to quickly prevent clotting, thereby avoiding heart attacks and strokes, as well as the fact the drug’s effect can also be reversed, which can be required in certain circumstances.

As well as proving comparable and hopefully superior efficacy to Plavix, given the serious concerns about excessive bleeding associated with Effient which has significantly reduced its commercial prospects, the safety profile of elinogrel will be just as important.

Although there are not that many similar products in active development, elinogrel is trailing behind two potentially significant competitors in AstraZeneca’s AZD6140 (ticagrelor) and The Medicines Company’s cangrelor, both currently in phase III trials and expected to be launched next year.
 

Platelet Aggregation Inhibitors: key pipeline projects
Phase Product Generic Name Pharmacological Class Originator Company First Introduction WW Peak Sales ($m)
Phase III AZD6140 ticagrelor P2Y12 antagonist Astra AstraZeneca 31/12/2010 -
  Cangrelor cangrelor P2Y12 antagonist AstraZeneca The Medicines Company 31/12/2010 474
  Anti-platelet compound - Platelet aggregation inhibitor Servier Servier - -
  Thromboxane Antagonist - Thromboxane A2 receptor antagonist Servier Servier - -
  CGT-2168 clopidogrel & omeprazole Platelet ADP antagonist Sanofi/Astra Cogentus Pharmaceuticals - -
  IND-702 - Phosphodiesterase & thromboxane synthase inhibitor Nissan Chemical Industries Indigo Pharmaceuticals - -
               
Phase II DG041 - Prostaglandin EP3 antagonist deCODE genetics deCODE genetics - 1,000
  Saratin - Platelet aggregation inhibitor Merck KGaA BioVascular - -
  PRT060128 elinogrel Platelet ADP antagonist Portola Pharmaceuticals Portola Pharmaceuticals - -
               
Phase I APD791 - 5HT2A (serotonin) antagonist Arena Pharmaceuticals Arena Pharmaceuticals - 300
  CS-8080 - Platelet aggregation inhibitor Daiichi Sankyo Daiichi Sankyo - -
  PR-15 - GP IV antagonist ProCorde Takeda - -
  ALX-0681 - Platelet aggregation inhibitor Ablynx Ablynx - -
  Aspirin-PC aspirin & phosphatidylcholine Cyclo-oxygenase inhibitor Bayer/Cutter labs PLx Pharma - -

As such, the phase IIb data for elinogrel at the end of 2009 will provide a critical point at which to determine whether Novartis’ $75m upfront fee was money well spent.

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