Therapeutic focus - Rheumatoid arthritis pipeline full but deals dropping off


The increasing incidence of rheumatoid arthritis caused by ageing Western populations is set to drive demand for drugs that treat both the disease itself and the symptoms, from non-prescription NSAIDs up to complex and expensive biological anti-TNF therapies.

As such, the pipeline of experimental drugs targeting RA is pretty full, with 4 novel compounds in late stage trials, and 51 in phase II (see table below). However, despite the huge success of the anti-TNF class, much hope is being held out for a break though in new oral remedies, and the first truly efficacious drug to reach the market in this segment is likely to be very successful.

The table below shows that oral approaches represent around half the approaches under development, at least in phase II and III. Pfizer is the most advanced with CP-690,550, a JAK-3 inhibitor which entered phase III in February.

Count of pipeline RA products
Phase Product Count  Route of Admin
Oral  Injection  Unclassified   
Phase III 4 2 2 -
Phase II 51 23 20 8
Phase I 44 15 15 14
Pre-clinical 121
Research project 39
Total active projects 259
Abandoned - Phase III 4
Abandoned - Phase II 50
Abandoned - Phase I 37
Abandoned - Pre-clinical 36
Abandoned - Research project 13
Abandoned - Unclassified 80
Total abandoned projects 220
Total pipeline 479

Eisai’s iguratimod appears to be a complex molecule described as being anti-TNF, IL-1, IL-6, IL-8 and a COX-2 inhibitor.

Not far behind, however is Rigel’s R788, which is close to announcing the final set of phase IIb data (Event - Rigel looking strong as second data set approaches, July 10, 2009). A partner is being sought, and considering the drug is the only Syk inhibitor in clinical development, could attract some attention. With the majority of the big pharma names already present on the list, any number of parties are likely to be taking a look.

Rheumatoid Arthritis Market - key pipeline products WW annual sales ($m)
Phase Product Generic Name Company (s) Pharmacological Class Route of Admin Lead Indication Summary Launch WW 2010 2012 2014
Phase III Arzerra ofatumumab GlaxoSmithKline + Genmab Anti-CD20 MAb Injection CLL [Filed]; NHL [Phase III]; RA [Phase III]  -  113  355  624
PRO70769 (R1594) ocrelizumab Roche + Biogen Idec Anti-CD20 MAb Injection RA [Phase III]; SLE [Phase III]; MS [Phase II]; NHL [Phase II]  Dec-2010  -  223  543
CP-690,550 - Pfizer Janus kinase-3 (JAK-3) inhibitor Oral RA [Phase III]  Dec-2011  -  100  380
Kolbet / Careram (T-614) iguratimod Eisai + Taisho Toyama Pharmaceutical JV  Anti-TNF, IL-1, IL-6, IL-8 & COX-2 inhibitor Oral RA [Phase III]  Dec-2012  -  57  69
 Phase II Denosumab (AMG 162) denosumab Amgen Anti-RANKL MAb Injection OA [Filed]; Bone repair & regeneration [Filed]; Bone metastases [Filed]; RA [Phase II]  -  411  2,152  3,648
Benlysta belimumab Human Genome Sciences + GlaxoSmithKline Anti-B lymphocyte stimulator (BLyS) MAb Injection SLE [Phase III]; RA [Phase II]  -  17  69  185
Atacicept atacicept Merck KGaA + ZymoGenetics B lymphocyte stimulator (BLyS) & a proliferation-inducing ligand (APRIL) inhibitor Injection SLE [Phase III]; RA [Phase II]; MS [Phase II]  -  -  16  33
TRU-015 - Wyeth + Trubion Pharmaceuticals CD20 inhibitor Injection RA [Phase II]  Dec-2013  -  -  20
BMS-582949 - Bristol-Myers Squibb p38 MAP kinase inhibitor Oral Psoriasis [Phase II]; RA [Phase II]  -  -  -  19
PH-797804 - Pfizer p38 MAP kinase inhibitor Oral RA [Phase II]; COAD/COPD [Phase II]; Post-herpetic neuralgia [Phase II]  Dec-2012  -  -  11
RhuDex - MediGene + Active Biotech CD80 antagonist Oral RA [Phase II]  Dec-2012  -  -  3
681323 dilmapimod GlaxoSmithKline p38 MAP kinase inhibitor Oral COAD/COPD [Phase II]; RA [Phase II]  Dec-2012  -  -  -
856553 losmapimod GlaxoSmithKline p38 MAP kinase inhibitor Oral COAD/COPD [Phase II]; RA [Phase II]  Dec-2012  -  -  -
PG-760564 - Procter & Gamble p38 MAP kinase inhibitor Oral RA [Phase II]  -  -  -  -
PS540446 - Ligand Pharmaceuticals p38 MAP kinase inhibitor Oral Psoriasis [Phase II]; RA [Phase II]; Atherosclerosis [Phase II]  -  -  -  -
R406/R788 fostamatinib Rigel Pharmaceuticals Syk kinase inhibitor Oral RA [Phase II]; Thrombocytopaenia [Phase II]; NHL [Phase II]  Dec-2011  -  -  -

However, the table below shows that deals for RA have dropped off considerably this year.

Product Deals for RA Drugs
Deal Date Deal Count
2009 (YTD) 2
2008 16
2007 19
2006 23
2005 13
2004 25
2003 21
2002 18
2001 29
2000 23
Total 189

Only two deals have been struck so far this year, the most recent being Purdue Pharma and Nitec, the former buying European rights to Lodotra, a slow release formulation of prednisone. The other deal was struck by Roche, which licensed Synta Pharmaceuticals’ CRACM inhibitor programme, which is still only a research project, but are orally bioavailable, paying $26m upfront.

This decline in deals could possibly be due to the huge success of the anti-TNF approach, which has deterred development of the competition. Sales of Abbott Laboratories' Humira are seen doubling by 2014 to $9.0bn, when Enbrel, sold by Wyeth and Amgen, is forecast to be a generating $6.5bn. Although it should be remembered these drugs are also sold for other autoimmune diseases such as psoriasis and Crohn's disease.

Of the 259 RA products in development, just 11 are TNF inhibitors. Clearly the focus has shifted elsewhere, and perhaps until these new approaches have demonstrated they can stand up to the TNFs in terms of efficacy, deal levels will not return.

In fact, the R&D landscape is becoming increasingly dominated by p38 MAP kinase inhibitors, which are shaping up to replace the anti-TNFs in terms of R&D dollar spend. GlaxoSmithKline, Bristol-Myers Squibb and Pfizer are currently developing the most advanced of these orally-delivered, p38 MAP kinase inhibitors.

Leading Classes of active Pipeline RA Drugs
Pharmacological Class Count of products
 p38 MAP kinase inhibitor  14
 TNF inhibitors / Anti-TNF MAb  11
 NF-kB inhibitor / modulator  7
 CD20 inhibitors / Anti-CD20 MAb  6
 Janus kinase-3 (JAK-3) inhibitor  5
 Anti-IL-17 MAb  4
 CCR1 antagonist  4
 IKK-beta inhibitor  4
 Melanocortin (MC) receptor agonist  4
 P2X7 ion channel antagonist  4

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