Positive phase II data for Human Genome Sciences (HGS) Benlysta (formerly LymphoStat-B) not only provided a welcome boost for shares in HGS, it also raised hopes that a disease modifying treatment could yet be established for lupus, a major unmet clinical need.
Following the recent high-profile phase III failures of Roche’s Rituxan and La Jolla’s Riquent, hopes for a breakthrough therapy for one of the hardest to treat medical conditions have been severely dented. However, the fact that Benlysta is one of 7 candidates in late-stage development, with 46 active research projects in total, suggests that at least a number of crucial shots at goal are being lined up which will hopefully deliver the first new treatment for lupus in over 40 years (see tables below).
Lupus is a chronic, life-threatening autoimmune disease which affects approximately 1.5 million people in the United States and 5 million worldwide. Symptoms of lupus include extreme fatigue, painful and swollen joints, unexplained fever, skin rash and kidney problems and can lead to arthritis, kidney failure, heart and lung inflammation, and blood disorders.
Currently the only approved drugs for lupus are immunosuppressant agents, such as Astellas Pharma’s Prograf and Roche’s CellCept, and corticosteroids such as prednisone. However, these products only treat the symptoms of the disease and can generate serious side effects.
Therefore a new wave of candidates, mainly monoclonal antibodies (MAbs), have been developed to try and treat the underlying causes of the autoimmune process to at least put the brakes on disease progression.
The following table, taken from EvaluatePharma’s pipeline portfolio analysis, illustrates the overall portfolio of products in active and failed development for lupus.
|Count of product portfolio for lupus|
|Abandoned - Phase III||2|
|Abandoned - Phase II||2|
|Abandoned - Phase I||2|
|Abandoned - Pre-clinical||5|
|Abandoned - Unclassified||15|
With 15 candidates in clinical trials and a decent clutch of 27 pre-clinical projects, a number of potential shots on goal are possible, although the phase III failures of Rituxan (Rituxan deals new lupus therapies a blow, April 30, 2008) and Riquent (La Jolla drug failure leaves few options, February 12, 2009) will no doubt keep a lid on expectations.
MAbs to the fore
Of the 15 clinical stage candidates, eight are MAbs which target a number of different immune response pathways.
|Clinical pipeline for Systemic lupus erythematosus (SLE) (sales aggregated across all indications)||WW annual sales ($m)|
|Market Status||Product||Generic Name||Company||Pharmacological Class||Lead Indication Summary||2008||2010||2012||2014|
|Phase III||Orencia||abatacept||Bristol-Myers Squibb||Anti-b7 integrin MAb||Arthritis, rheumatoid [Marketed]; Crohn's disease [Phase III]; Ulcerative colitis [Phase III]; SLE [Phase III]||441||787||1,143||1,436|
|PRO70769 (R1594)||ocrelizumab||Roche + Biogen Idec||Anti-CD20 MAb||Arthritis, rheumatoid [Phase III]; SLE [Phase III]||-||-||233||352|
|Benlysta (LymphoStat-B)||belimumab||Human Genome Sciences + GlaxoSmithKline||Anti-B lymphocyte stimulator (BLyS) MAb||SLE [Phase III]||-||3||83||260|
|Epratuzumab (IMMU-103)||epratuzumab||UCB + Immunomedics||Anti-CD22 MAb||SLE [Phase III]||-||-||22||34|
|Atacicept||atacicept||Merck KGaA + ZymoGenetics||B lymphocyte stimulator (BLyS) & a proliferation-inducing ligand (APRIL) inhibitor||SLE [Phase III]||-||-||16||33|
|Phase II||MEDI-545||sifalimumab||Medarex + AstraZeneca||Anti-interferon alpha MAb||SLE [Phase II]||-||-||-||-|
|Lupuzor||-||Cephalon + ImmuPharma||Immunomodulator||SLE [Phase II]||-||-||-||-|
|Phase I||Actemra||tocilizumab||Roche + Chugai||Anti-IL-6 MAb||Arthritis, rheumatoid [Marketed]; Multiple myeloma [Phase II]; Crohn's disease [Phase II]; SLE [Phase I]||-||454||1,613||3,106|
|Paquinimod (57-57)||paquinimod||Active Biotech||Immunomodulator||SLE [Phase I]||-||-||-||-|
|Anti-IFN alpha||rontalizumab||Roche||Anti-interferon alpha MAb||SLE [Phase I]||-||-||-||-|
|SBI-087||-||Wyeth + Trubion Pharmaceuticals||CD20 inhibitor||Arthritis, rheumatoid [Phase I]; SLE [Phase I]||-||-||-||-|
|AMG 557||-||Amgen||B7 related protein (B7RP-1) inhibitor||SLE [Phase I]||-||-||-||-|
|AMG 811||-||Amgen||Anti-interferon gamma MAb||SLE [Phase I]||-||-||-||-|
|CPG 52364||-||Pfizer||TLR7, 8 & 9 antagonist||SLE [Phase I]||-||-||-||-|
|A-623||-||Anthera Pharmaceuticals||B-cell activating factor (BAFF) inhibitor||SLE [Phase I]||-||-||-||-|
Benlysta is a MAb which targets the B-lymphocyte stimulator to prevent the production of auto-antibodies which is one of the underlying causes of lupus.
Although the phase II data for Benlysta is encouraging, the drug has yet to pass its biggest test with phase III results from two trials due to be released in July and November this year.
Roche and Biogen Idec’s ocrelizumab is a follow-on MAb to Rituxan and as such expectations for this drug being a success for lupus remain relatively low. Following the failure of Rituxan last year Roche abandoned an ongoing phase III trial of ocrelizumab in lupus patients. However, a new phase III trial of ocrelizumab in 369 patients with lupus nephritis was initiated in January and the hope must be that lessons learnt from Rituxan’s failure can deliver a more successful outcome this time round.
Although Immunomedics’ epratuzumab has previously reached phase III trials, manufacturing issues in 2006 delayed the development of the product. A pivotal phase IIb trial recently completed enrolment and data is expected in the first quarter of 2010.
Merck KGaA’s atacicept, licensed from ZymoGenetics and the only non-MAb product in phase III, is currently being tested in phase II/III trials for systemic lupus erythematosus (SLE); the product had a setback last November when a phase II/III trial for lupus nephritis was abandoned.
Bristol-Myers Squibb’s Orencia, already approved to treat rheumatoid arthritis, is undergoing phase II/III trials in patients with active lupus nephritis. The study was initiated in 2007 but is not due to complete until May 2011, suggesting Orencia is slightly behind its phase III counterparts.
Limited partnering opportunities
What is interesting about the clinical stage pipeline of products for lupus is that all but 2 of the 15 candidates have already been partnered or are in the hands of a big pharma company. Although lupus is a somewhat niche and specialist area, it is clear that the size of the market and unmet medical need has certainly attracted a number of big players.
The only clinical products that have yet to find a partner are Anthera Pharmaceuticals’ A-623 and Active Biotech’s 57-57 (paquinimod). Active Biotech recently pulled a plan to start a large phase II/III trial of 57-57 and are instead seeking a partner to takeover all further clinical development.
Companies wishing to enter this field will therefore have to make an earlier and riskier bet by dipping in to the pre-clinical pool.