Chi-Med (HONG KONG, China), the Hutchison Whampoa-backed pharmaceutical and healthcare group, announced positive results for its phase II proof-of-concept study for HMPL-004 in mild-to-moderate ulcerative colitis (UC).  The phase II, multicenter, randomized, double-blind, comparator study of 120 patients with mild-to-moderate UC  was conducted in China by Chi-Med's wholly-owned drug R & D subsidiary, Hutchison MediPharma Ltd.

The study evaluated HMPL-004 at 400 mg taken orally three times a day for 8 weeks, compared with mesalazine, the current first-line standard of care in mild-to-moderate UC, which is  effective in about 60% of treated patients. The four trial endpoints were the clinical symptom score, the overall clinical evaluation, the colonoscopic score, and safety evaluation. After treatment was completed in the intent-to-treat patient group, the clinical symptom score reduction for HMPL-004 was 56% versus 59% for mesalazine, the overall remission rate (a combination of complete and partial remissions) for HMPL-004 was 57% by clinical score versus 53% for mesalazine, and 47% for HMPL-004 versus 42% for mesalazine by colonoscopic score. HMPL-004 was well tolerated in the study and the adverse event (AE) rate was half that of the mesalazine group.

Chi-Med's preclinical work with HMPL-004 has shown that HMPL-004 acts on multiple cellular targets in the inflammatory signal transduction pathways, resulting in suppressed inflammation cytokine expression including TNF-alpha, IL-1beta, and IL-6. HMPL-004 inhibited TNF-alpha and IL-1beta production in cell-based assays and also NF-kB activation. In preclinical models of inflammatory bowel disease, treatment of rats with HMPL-004 caused a significant drop in plasma cytokine concentrations, including TNF-alpha and IL-1beta.  Preclinical trials for HMPL-004 have shown the almost total restoration of the inner lining of the gut.

The company believes that HMPL-004, which has a mechanism of action different from mesalazine yet similar efficacy, is a potential alternative treatment option for UC patients who either are  not responding to mesalazine or who develop resistance over long-term use.

HMPL-004 is an orally active, proprietary botanical compound extracted from an undisclosed Chinese herb that has an extensive history of use in China and Southeast Asia in traditional remedies to treat upper respiratory infections and other inflammatory and infectious diseases. This documentation enabled Chi-Med to bypass phase I trials and accelerate the clinical process for HMPL-004, on the basis of the US FDA's 2004 guidance on botanical drug products, which allows for an accelerated and cost-efficient process for the US registration of such botanical drugs.

 Extracts of the same herb have also been used in the past as dietary supplements in the US.  Among an estimated 129 million users in China over 16 years, a total of only 15 cases of AEs are documented. A search of US FDA databases found no reports of AEs associated with the dietary supplement use of extracts from the same herb source as HMPL-004.

HMPL-004 is currently also in a phase II, double-blind, randomized, multicenter, placebo-controlled study in the US to determine the compound's efficacy and safety in both male and female subjects with active, moderate Crohn's disease. Chi-Med intends to out-license HMPL-004 following successful completion of the phase II study.

Hutchison MediPharma also has a pipeline of single molecular entity discovery projects in autoimmune and/or inflammatory diseases (including lupus) that  have shown activity against clinically validated targets.

—A. Techman

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