Gur Roshwalb, M.D.

Despite past failures, the search for drugs that can inhibit the inflammatory proteins continues unabated.

Secretory phospholipases A2 (sPLA2) are inflammatory proteins known to play a role in the pathogenesis of many inflammatory diseases. They are a subfamily of PLA2 enzymes that catalyze the hydrolysis of phospholipids, yielding precursors of pro-inflammatory lipid mediators including bioactive eicosanoids and platelet-activating factor (PAF). sPLA2 inhibitors hold an established role in inflammation treatment, since inhibition of sPLA2 would in theory prevent the formation of inflammatory eicosanoids prior to the cyclooxygenase (COX) reaction. To date, the complexity of these proteins has made it a challenge to develop a successful class of sPLA2 inhibitors, although new approaches open the possibility of future success.

The development of sPLA2 inhibitors as potential anti-inflammatory agents has been extensively pursued since the release of arachidonic acid from membrane phospholipids by PLA2 is one of the rate-limiting factors for eicosanoid production. In addition to the production of eicosanoids, PLA2-catalyzed membrane phospholipid hydrolysis is also the initiating step in the generation of PAF, a potent inflammatory agent. Thus, inhibition of PLA2 activity should, in theory, be a more effective anti-inflammatory approach. Furthermore, one of the pathways through which corticosteroids are suspected of exerting their anti-inflammatory effects is through sPLA2 inhibition via lipocortin induction. However, developing an inhibitor that would be selective for the production of inflammatory metabolites and not inhibit the beneficial properties of PLA2 has so far proved to be elusive.

Inhibition of specific PLA2 isoforms is potentially an effective therapy for several inflammatory conditions and has been actively explored for several years. Despite this, there are no selective PLA2 inhibitors clinically available to date. The identification and characterization of additional members of the expanding PLA2 family and development of more selective PLA2 inhibitors has not served to elucidate a clinically effective anti-inflammatory role for PLA2 inhibition as was previously hoped. The development of a cell-impermeable sPLA2 inhibitor that would protect the cell membrane from sPLA2 activity without affecting vital intracellular PLA2 activity was proposed to be an effective therapeutic avenue several years ago, but has not borne fruit.

As a recognized target of inflammation research, sPLA2 has resulted in several failed approaches in trials conducted by the pharmaceutical industry. For example, Eli Lilly & Co. has conducted analyses of LY315920NA/S-5920, a selective inhibitor of sPLA2 subtype IIA, to address inflammation related to asthma, arthritis, and sepsis. In a previous study, LY315920NA/S-5920 was well-tolerated and appeared to improve survival in a subgroup of patients who received the drug within 24 hours of first sepsis-induced organ failure.

A subsequent Lilly study was designed to determine whether improvement in survival could be confirmed in a larger patient population meeting the characteristics of that subgroup. The study was terminated after data on 250 patients—with at least two sepsis-induced organ failures—suggested a significant improvement in 28-day all-cause mortality would not be found if the trial continued as planned. The mortality rate was 39.4 percent in the LY315920NA/S-5920 group, compared with 31.9 percent in the placebo group (p = .092). Additionally, Anthera Pharmaceuticals studied sPLA2 inhibition for acute coronary syndrome also using LY315920NA/S-5920, but the trial failed in Phase III.

A separate research program, conducted by Wyeth Pharmaceuticals, focused on inflammation associated with the central nervous system and arthritis. The program was terminated when it was found that the compound being tested was inhibiting the cPLA2 family, a cousin to sPLA2 that is homeostatic and vital to the cell.

It is vital to inhibit the correct sPLA2 isomers, of which there are approximately 12, not just one or two most ubiquitous ones. It is also important not to interfere with the cPLA2 family. A novel group of compounds called Multi-Functional Anti-Inflammatory Drugs (MFAIDs) have been rationally designed and synthesized to overcome these two critical problems and represent not just a single molecule but an entire new genus of compounds, each different but with a similar mechanism of action. MFAIDs might offer effective treatment for a wide range of inflammatory diseases including conditions with pulmonary inflammation like cystic fibrosis, inflammatory skin diseases such as eczema, inflammatory bowel disease, and ophthalmic inflammatory conditions such as conjunctivitis and dry eye. To date, MFAIDs have shown in vitro and in vivo efficacy in numerous models and patients.

As more information becomes available regarding the role of PLA2 isoforms—including sPLA2—in different cells and tissues, the medical community looks forward to developing additional enhanced selective inhibitors. For example, as more information becomes available concerning the structure, functional sites and modulators of activity, selective sPLA2 inhibitors might be developed to specifically target functional groups on the enzyme other than the catalytic site or to target alternative intracellular sites. Additionally, studies that demonstrate inhibition of sPLA2 activity under experimental conditions might identify alternative avenues to explore for therapeutically suitable sPLA2 inhibitors.

The continuing study of sPLA2 as a target of inflammation research is bound to inspire innovation in the years to come. 

Gur Roshwalb, M.D ([email protected])., is CEO of Celsus Therapeutics.

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