Developing Multi-Functional Anti-Inflammatory Drugs
Thu, 07/24/2014 - 10:44am
Recent years have witnessed the development of novel, non-steroidal anti-inflammatory drugs termed Multi-Functional Anti-Inflammatory Drugs (MFAIDs). The focus has been on one of the most sought-after pharmaceutical targets in inflammation research: the secretory phospholipase A2 (sPLA2) family.
sPLA2 is an extracellular family of enzymes that serves as a universal early trigger in inflammatory responses that hydrolyze phospholipids on the cell membrane into two key inflammatory precursors: arachidonic acid (AA) and lysophospholipids (LysoPL).
AA is metabolized via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways to produce large families of eicosanoids; many of them are involved in the development of pathological conditions, especially in inflammation-related processes. These include prostaglandins, thromboxanes and leukotrienes.
Meanwhile, LysoPL induce white cell activation and extravasation, activate cell activation (by lyso phosphatidylserine in particular), induce tissue damage such as gastric ulceration, and act as growth factors (especially lyso phosphatidic acid), to induce proliferation of cancer cells and tumor metastasis. Furthermore, LysoPL are also the precursors of platelet activating factor (PAF), possibly the most potent mediator of inflammatory processes.
The key to successfully controlling this “universal inflammatory trigger” has been demonstrated by the past clinical failures of several pharmaceutical companies. 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 calcium-dependent phospholipase A2 (cPLA2) family, a related group of enzymes that are located inside the cell—unlike sPLA2—and that have a vital homeostatic role—again, unlike sPLA2—that must not be interfered with.
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 (CF); inflammatory skin diseases such as eczema; inflammatory bowel disease (IBD); and ophthalmic inflammatory conditions such as conjunctivitis and dry eye.
MFAIDs in Atopic Dermatitis
MFAIDs have shown in vitro and in vivo efficacy in numerous models and patients. A potential indication for MFAIDs is atopic dermatitis (also known as eczema), which is a common condition. One leading drug candidate is a topical cream (MRX-6) currently being tested in a Phase 2 trial in pediatric atopic dermatitis on the basis of positive findings in two Phase 2 studies of patients with chronic hand eczema. Results are expected during the fourth quarter of 2014.
Conventionally, steroids have been prescribed to treat the symptoms of atopic dermatitis. Unfortunately, prolonged use of steroids can lead to unwanted side effects such as tachyphylaxis (tolerance to vasoconstriction), rosacea, skin atrophy and stretch marks. Additionally, short stature and suppression of the hypothalamic-pituitary-adrenal axis in children are continuing concerns for patients and physicians alike. Long-term steroid use can also promote the development of infections. To counteract the limitations of steroid treatment, some physicians have prescribed topical calcineurin inhibitors, which in turn carry a cancer risk and can suppress the immune system. As a result of the lack of effective alternatives to steroids, there is a serious unmet need for treatment of atopic dermatitis.
MFAIDs in Other Conditions
MFAIDs have a structure that is particularly attractive for ophthalmological formulation and have shown preclinical safety and efficacy for treating conjunctivitis and dry eye in animal studies. One compound is a topical treatment in eye drop form, targeting inflammation affecting the surface of the eye (conjunctiva) such as Dry Eye Syndrome and allergic conjunctivitis, both seasonal and perennial. Positive data on guinea pig conjunctivitis as well as a safe ocular toxicology profile have been obtained.
Published data also exist in the standard industry animal model in asthma—the rat ovalbumin allergic bronchitis model—showing amelioration in symptoms, histology and inflammatory mediators.
A preclinical program in IBD has demonstrated the efficacy of MFAIDs orally administered in both in vitro and in vivo in both the dextran sulfate sodium (DSS) and tinitrobenzene sulfonate-based IBD animal models. Both injection and oral administration were effective in animal models.
Finally, a preclinical program in CF generated positive data in CF cell lines. MFAIDs have produced promising results in the standard cellular assays for CF, demonstrating inhibition of interleukin (IL)-8 production, a key inflammatory mediator in CF. One MFAID will target the underlying inflammatory causes of CF pathophysiology and aims to provide a safe, chronic treatment to CF patients that will reduce pulmonary inflammation and mucus secretion and provide for improved breathing and quality of life.
If work on MFAIDs prospers, it could offer new options for patients experiencing various types of inflammation and who wish to avoid the risks of steroids.