HMPL-004 is a novel oral drug product in development for Inflammatory Bowel Diseases (IBD) and derived from a botanical extract. The clinical efficacy and safety of HMPL-004 in the treatment of mild-to-moderate IBD has been demonstrated in over 400 patients in Phase II trials conducted in North America, Europe and Asia. Phase III studies in ulcerative colitis were initiated in April 2013 but were terminated in August 2014 following an interim analysis. HMP and its partner, Nestle Health Science, continue to review and discuss the data and are working towards agreeing next steps.
Mechanism of Action
HMPL-004 acts on multiple cellular targets in the inflammatory signal transduction pathways resulting in suppressed inflammation cytokine expression including TNF-α, IL-1β and IL-6. HMPL-004 was demonstrated to inhibit TNF-α and IL-1β production in cell-based assays. HMPL-004 is also able to inhibit NF-кB activation. NF-кB is a family of transcriptional factors that regulate a wide spectrum of genes critically involved in host defence and inflammation. The mechanism of action of HMPL-004 was further supported in laboratory IBD animal models. Treatment of IBD rats with HMPL-004 caused a significant drop in plasma cytokine concentrations, including TNF-α and IL-1β.
Proof-of-Concept Clinical Experience in Inflammatory Bowel Disease
In November 2009, a Phase IIb Ulcerative Colitis (“UC”) trial was successfully completed. The trial was a multi-center, double-blind, randomized and placebo-controlled study conducted in 223 UC patients in the United States, Canada and Europe. The three-armed clinical trial included 8 weeks treatment of HMPL-004 at two dose levels, 1200 mg/day or 1800 mg/day, vs. placebo. The primary efficacy endpoint of the trial was clinical response. The secondary endpoints included clinical remission and the mucosal healing rate. The safety profile of the drug was also assessed.
The study clearly succeeded in meeting all the endpoints, as demonstrated in the figure below. HMPL-004 also demonstrated an excellent safety profile at both dose levels. There were no treatment-related serious adverse events in either of the HMPL-004 arms reported by the investigators. The results were presented in a Distinguished Plenary presentation during the 2010 Digestive Disease Week conference by Dr. William J. Sandbom, Professor of Medicine at the Department of Gastroenterology & Hepatology of the Mayo Clinic.
In May 2007 HMPL-004 completed a multi-center, randomized, double-blind, and comparator-controlled Phase II proof-of-concept study of 120 patients with mild-to-moderate Ulcerative Colitis. The study evaluated HMPL-004 at 400mg taken three times a day, orally, compared to Mesalazine, the current first-line standard of care. The four trial endpoints were patients’ clinical symptom score; overall clinical evaluation; colonoscopic score; and safety evaluation. After treatment for eight weeks, the percentage of patient’s clinical symptom score reduction for HMPL-004 was 56% versus 59% for Mesalazine in the Intent-To-Treat population. The overall remission rate (combination of complete and partial remissions) for HMPL-004 was 57% by clinical score compared to 53% for Mesalazine in the Intent-To-Treat population and 47% for HMPL-004 versus 42% for Mesalazine by colonoscopy in the Intent-To-Treat population. HMPL-004 was well tolerated in the study and the adverse event rate was half that of the Mesalazine group.
US FDA IND clearance was received in 2005 for a Phase II study on HMPL-004 for the treatment of patients with Crohn’s Disease (“CD”). The study was a multi-centre, double blind, randomized, and placebo-controlled study conducted in 101 CD patients in the United States and Ukraine. The results demonstrated an encouraging trend of efficacy and a good safety profile.
Inflammatory Disease Market
UC and CD are the two most common forms of IBD. The patient population with UC and CD in the US is estimated to be between 250,000-500,000 and 400,000-600,000 respectively. The annual incidences of UC and CD in the US are 2-7 cases per 100,000 population per year and 5-7 cases per 100,000 population per year, respectively. Between 2001 and 2005 it is estimated that the number of patients with UC in the US increased by approximately 47,000, representing a CAGR of 4 percent and the number of patients with CD increased by approximately 58,000, a CAGR of 3 percent.
Key Advantages of HMPL-004
- Belongs to the same family of inflammatory cytokine inhibitors as infliximab (Remicade™), which has had success in similar indications, yet HMPL-004 does not demonstrate the same degree of adverse events.
- An oral agent rather than an injection, unlike most antibody therapies.
- In Inflammatory Bowel Diseases, phase IIb clinical data demonstrates potential for both first line and mesalamine failure patients.
- A long history of human use of the herb from which it is derived, three completed phase II studies in over 400 patients, and various animal safety studies suggest that the product is well-tolerated with a good safety profile.
- Extracted from a single herb and formulated as a solid dosage form, HMPL-004′ s cost per therapy is lower than existing antibody therapies.
HMPL-004 is prepared and manufactured through a highly exclusive, proprietary process and is covered by well over 30 patents and patent applications worldwide.