Multi-faceted drug adds arthritis string to its bow

By Mike Nagle

- Last updated on GMT

Related tags: Inflammatory bowel disease, Inflammation

A UK biopharma firm's lead drug candidate has now shown good
preclinical results for rheumatoid arthritis, adding to its
clinical efficacy in Alzheimer's.

Hunter-Fleming has developed HF0220, which is based on a natural occurring compound. Its potent anti-inflammatory effects could enable it to treat a wide variety of degenerative diseases that, as well as arthritis and Alzheimer's, also includes stroke, heart disease, inflammatory bowel disease (IBD) and psoriasis. The drug causes a group of pro-inflammatory signalling molecules, called prostaglandins, to be reduced. Other drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) also have this effect, through blocking either or both of the molecules that produce prostaglandins: cyclooxygenase (COX1 and COX2). However, the problem with NSAIDs is that they also prevent anti-inflammatory prostaglandins from being produced. What sets HF0220 apart is that it not only suppresses pro-inflammatory prostaglandins but also increases levels of anti-inflammatory ones. Hunter-Fleming's CEO Mike Capaldi told DrugResearcher.com that he believes this mechanism of action is unique. In this most recent preclinical rheumatoid arthritis research, levels of the anti-inflammatory prostaglandin J2 (15d-PGJ2) increased four-fold whilst levels of pro-inflammatory prostaglandin E2 (PGE2) were halved. In effect, this prevented almost all of the disease from occurring in the joints, meaning joint destruction was inhibited in 90 per cent of the animals tested after 60 days. Capaldi described PGE2 as one of the main drivers of prostaglandin inflammation, which gives rise to pain, heat, swelling and other symptoms. Capaldi went on to explain that HF0220 (7-beta-hydroxyepiandrosterone, 7-beta-OH-EPIA) is normally produced in small amounts in the brain and possibly also in peripheral tissue of many mammals. Steroids are often associated with unpleasant side-effects, yet Capaldi said: "It is very 'unsteroid like'.It doesn'tshow any specific binding to any classical steroid hormone and glucocorticoid receptors and shows no classical steroid effects." "Also,"​ he continued, "unlike other steroids, or indeed other disease modifying anti-arthritic drugs [such as TNF antibodies, NSAIDs, andmethotrexate],HF0220 has shown no side effects even when administered at doses up to one hundred times the therapeutically active dose." ​ Thanks to these advantages, he expects HF0220 to have "significant safety advantages"​ over other drugs. PGJ2 is the body's natural resolution to inflammation and inhibits PGE2 synthase - the protein that produces PGE2. It is also the natural ligand of the peroxisome proliferator-activated receptor gamma (PPAR-gamma). Therefore, by increasing PGJ2 and decreasing PGE2, Hunter-Fleming hopes that HF0220 can effectively 'switch of' inflammation and then activate the body to begin repairs. The company is still working on exactly how HF0220 does this but the drug is currently being tested against Alzheimer's disease in a Phase IIa trial - as the protein that produces HF0220 is missing in the brain's of Alzheimer's sufferers, so it has been postulated that replacing the lost molecule could have a positive effect through increasing levels of 15d-PGJ2 and PPAR-gamma activation. This can then prevent the beta-amyloid stimulated inflammation and nerve cell death. It also being tested in a bridging Phase I study; another Phase I was needed as the company is changing the formulation from a suspension to a gel filled capsule. It will then begin a Phase II trial in either against inflammatory bowel disease (IBD) or rheumatoid arthritis in the second half of 2008. It has also been run in preclinical tests against stroke. Here the clinical outcome is highly correlated to the survival of the penumbra - the area around the stroke site. So far, the researchers have seen that HF0220 can rescue almost all of this area - even if administered six hours after the stroke. Finally, Hunter-Fleming also hopes to begin clinical testing of a cream formulation to treat psoriasis in the near future. So far, the clinical results have been very promising with Capaldi claiming the company has not seen any side effects except in the placebo arm of the tests. Hunter-Fleming is also developing a range of second-generation synthetic drugs that are based on HF0220, but work better. Capaldi said the scientists are currently at the 'hit' stage of research and have developed their own assay based on human monocytes to test the drug candidates. This has enabled the company to strengthen the patent protection around HF0220 which, being a natural product, is not itself patentable.

Related topics: Preclinical Research

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