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Multi-Functional Anti-Inflammatory Drugs (MFAIDs): Small Molecule Invention of Dr. Saul Yedgar, HUJI and Yissum

Reporters: Larry H Bernstein and Aviva Lev-Ari, PhD, RN

Novel, non-steroidal, multifunctional approach to treating inflammatory/allergic diseases
Principal investigator and Inventor: Professor Saul YEDGAR

Professor Saul Yedgar

Walter & Greta Stiel Chair in Heart Studies

Department of Biochemistry

Hebrew University-Hadassah Medical School

Jerusalem, Israel 91120

Tel:   00972-2-643-9218 (office)

         00972-2-652-0159 (home)

Fax: 00972-2-675-7291

Email: yedgar@md.huji.ac.il

 

MFAID-Mechanism of Action-March-16

MFAIDs-Overview-Jan-2016

US Granted Venn Diagram

US Pending-Venn Diagram

The initiation of inflammatory/allergic processes involves two key activities:

1. Degradation of cell membrane lipids by the enzyme phospholipase A2 (PLA2), leading to a cascade of inflammatory lipid mediators (ILM), which includes two main families:

• prostaglandins (PGs) and
• leukotrienes (LTs),

produced via the COX and LOX pathways, respectively.
2. Degradation of the cell-surface protective layer composed of glycosaminoglycans (GAG) that protects cells and tissues from damaging agents, such as

• free radicals,
• endotoxins, and
• enzymes that promote the formation of cancer metastasis.

A common and conventional approach to treating inflammatory processes has been the development of drugs that suppress the inflammatory lipid mediators (ILM) formation or action, focusing primarily on the PG-producing COX pathways (COX inhibitors), assumed to be the predominant ones.
3. However, deleterious ILM are produced also by the other pathways. Therefore, the selective COX inhibition, represented by NSAIDs, has not been successful, and related drugs (e.g., VIOXX from Merck) have been withdrawn from the market.
4. On these grounds, the approach of “inclusive pathway inhibition” has been proposed, aiming at containing theinflammatory lipid mediators (ILM) production by all pathways, by controlling the PLA2 activity.

 

5. At the same time, while the pharmaceutical industry has focused on the ILM production, the role of the cell-surface GAGs in inflammatory/allergic pathology has been ignored.

6. To address both needs (controlling ILM production and enriching the cell surface GAGs), Inventor  designed and synthesized a platform of novel and unique compounds composed of

• PLA2-inhibiting lipid moieties conjugated to GAGs.

This structure enables the inhibiting lipid component to incorporate into the surface and anchor the conjugated GAG to the cell membrane.

These lipid-conjugates exert a dual protective effect:

• the PLA2-inhibiting lipid moiety suppresses the ILM production, and
• the membrane-anchored GAG enriches the cell surface protective layer.

This presents a platform of multi-functional anti-inflammatory drugs (MFAIDs) for the treatment of diseases associated with

• lipid mediator production and/or
• damage to cell surface.

The MFAIDs excellent safety been demonstrated in both

• pre-clinical and
• clinical data

generated with over 200 subjects that have been treated with MFAIDs in clinical trials.

Selected MFAIDs have been tested and found effective

• in the suppression of inflammatory/allergic processes in different cell types (see List of Selected Publications below), as well as
• in inhibiting the production and action of metastasis-promoting enzymes by human cancer cells.

Subsequently, the MFAIDS have been tested and found effective in treating diverse inflammatory conditions, in

• animal models and
• clinical studies

Clinical Trials (studies with patients and with human tissues):

a.  Contact dermatitis: Two clinical studies (presenting Phase I and Phase IIa/IIb, double blind) showed

excellent safety and efficacy in treating patients with contact dermatitis by topical application of MFAID.

b. Atopic Dermatitis (concluded on February 2015): Phase II clinical trial performed at Sheba Hospital in which patients with atopic dermatitis were treated with topical formulation (cream) of an MFAID (one dose).

Results showed no toxicity or adverse effects, but no significant efficacy

(should be retested using an appropriate formulation enabling a better penetration rate).

c. Airway Pathologies (see below)

Clinical Studies:

• Allergic Rhinitis in allergic patients (in South Africa), treatment by intra-nasal (IN) administration (spraying) of MFAID solution (saline) – one dose (Slides 23-28 in the presentation).   Excellent safety (better than placebo)   Marked suppression of challenge-induced biochemical markers, IL-5, IL-13 TNF-α, MCP-1 and Exotoxin, as well as eosinophil level, in nasal lavage.

11% improvement of symptoms.

• Chronic RhinoSinusitis (ex vivo), using Nasal polyps of patients suffering from Chronic RhinoSinusitis with polyps (CRSwP) (Slides 29-31 in the presentation).   Nasal polyps (cell dispersion) of patients suffering from CRSwP were stimulated with superantigen (SA = staphylococcus Aureus Enterotoxin).

Treatment with MFAID markedly suppressed

• the SA-stimulated.
• Production of IL-5, IL-13, IL-17 and to a lesser extent IFN-γ.
• Gene expression (mNBA) of secretory PLA2s, gIB, gII (A, D &E), and gX

 

• Broncho-Constriction

Prevention of OVA-induced broncho-constriction and airway resistance, as well as

• infiltration of inflammatory cells (cellularity) in the lung (histology).
• Suppression of the level of eicosanoids, including the broncho-constricting CysLts, PGD2 and TBX2, in BAL
  5-lipoxygenase (5-LO) protein expression in lung tissue.
• Gene expression (mRNA) of PLA2s (including sPLA2gX)

Advantages:

1. A platform of molecules with potential to synthesize many APIs and formulations
2. Multi-factorial anti-inflammatory/allergic mechanisms:

• Protecting cells from membrane phospholipid degradation, and
• Enrichment of the protective layer of cell surface glycosaminoglycans (GAG)

3. The technology is protected by a very extensive patent portfolio
4. Human clinical trails