Wednesday, January 18, 2006

BAFF & APRIL: Emerging Targets for Autoimmune & 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.

In the wake of the emerging success of therapeutics such as
LymphoStat-B and TACI-Ig our pharmaceutical analysts have produced an in depth drug discovery report BAFF & APRIL: Emerging Targets for autoimmune & Cancer Therapeutics

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.

Already interest in this report is strong and hopefully this indicates that further companies are entering the field of BAFF. This can only lead to further optimization of therapeutics from this class.

If you have found this post interesting you may also be interested in another one of our recent reports Autoimmune Disorders & Transplant Rejection


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