BAFF (BLys) & APRIL: Emerging Targets for autoimmune disease & Cancer Therapeutics

In 1999 Human Genome Sciences researchers published a study in the journal Science describing a new member of the TNF super-family which they named BLyS. Since that time our understanding of this protein, also known as BAFF, and its homologue APRIL has progressed rapidly. The BAFF sub-family has emerged as a candidate target for therapies of various autoimmune diseases and hematological cancers with breathtaking speed.

In April 2005, LymphoStat-B, HGS' neutralizing anti-BAFF monoclonal antibody, met the primary efficacy and safety endpoints in a Phase 2 clinical trial in patients with rheumatoid arthritis. A few months later a Phase 2 study also demonstrated efficacy in systemic lupus erythematosus. Earlier this month Zymogenetics announced Phase 1 data on TACI-Ig, a decoy receptor designed to block APRIL and BAFF. This molecule is also showing promising activity in hematological cancers.

The continuing success of Rituxan has established a proof of concept for the development of B-cell targeted therapeutics as treatments of a broad range of autoimmune disorders and hematological cancers and global annual sales are now well in excess of $2 billion. Therapeutics targeting the BAFF sub-family stand to offer significant competition to Rituxan yet advanced development is currently restricted to LymphoStat-B and TACI-Ig. LeadDiscovery’s analysts believe that this drug class is far from optimized, offering companies with an interest in autoimmune disease or cancer significant opportunities.

Our brand new drug discovery report BAFF & APRIL: Emerging Targets for autoimmune & Cancer Therapeutics offers a detailed look at BAFF and APRIL focusing on:

> A detailed but easy to understand backgrounder on B-cell immunology designed to bring all drug development personnel up to speed in this area

> Proof of concept for developing blockers of BAFF and/or APRIL. CD70, a homologue of these proteins, and it’s receptor CD27 are also evaluated briefly.

> Identification of target indications for BAFF and/or APRIL blockers

> Prevalence, current treatments and etiology of target indications

> Clinical data for BAFF blockers in advanced development

> Strategies for improving the efficacy of currently developed BAFF blockers

In short, if your company is looking to enter the emerging field of BAFF this report will provide all the key information necessary to help you fast track this process.

Some of our key conclusions are:

> There is particularly good evidence to support a role of BAFF in the etiology of rheumatoid arthritis although based on cross-study comparison the efficacy of the lead therapeutic in this class, LymphoStat-B, appears to be inferior to Rituxan. LymphoStat-B blocks just BAFF however APRIL is also elevated in the synovial fluid of rheumatoid arthritis patients. We conclude that dual blockade of APRIL as well as BAFF may be required for optimal therapeutic activity. Data from ZymoGenetic’ study of TACI-Ig may shed some light on this issue.

> Immunosuppressive adverse effects of BAFF/APRIL blockers should be less than those resulting from Rituxan

Blocking BAFF and/or APRIL may be a useful adjuvant to TNF blockers, increasing efficacy while possibly reducing the heightened risk of lymphoma associated with this major therapeutic class.

> There is good evidence to suggest that BAFF contributes to the etiology of systemic lupus erythematosus however optimal selectivity of therapeutic agents aimed at BAFF remains to be established.

> Of all the autoimmune conditions investigated, the serum levels of BAFF are highest in Sjögren's syndrome. > One particularly attractive advantage of blocking BAFF and/or APRIL is that this approach may prevent the development of lymphomas, a co-morbidity associated with a subgroup of patients.

> Other autoimmune diseases that have yet to fall under the spotlight of BAFF/APRIL should be evaluated as target indications. In particular multiple sclerosis and inflammatory bowel disease may represent potential indications.

> Strong evidence supports the blockade of BAFF/APRIL as a treatment of multiple myeloma and non-Hodgkin’s lymphoma. Elevated levels of these molecules may limit the efficacy of existing therapeutic agents, while their blockade is likely to act in an additive or possible synergistic fashion with steroids or IL-6 therapeutics.

Publication date: January, 2006
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