Randomized, Double-blind, Placebo-Controlled Trial of Andrographis Paniculata Extract (HMPL-004) in Patients with Moderately Active Crohnʼs Disease

Purpose: HMPL-004 is an extract of the herb Andrographis Paniculata, which inhibits pro-inflammatory cytokines including TNF-α, IL-1β, and NF-κB. We evaluated HMPL-004 for Crohn's Disease (CD). Methods: Patients with moderate CD (CDAI 220-400 + CRP > upper limit of normal) despite stable doses of concomitant medications were randomized to oral HMPL-004, 1200 mg/day or placebo for 8 weeks. The primary endpoint was clinical response-100 (CDAI reduction of 100 points) at 8 weeks. Secondary endpoints included response- 70 and remission (CDAI <150 points). Missing data were handled by worst observation carried forward. Results: One hundred and one patients were enrolled at 26 sites in the US and Ukraine (HMPL-004 n=51 and placebo n=50). At week 8 the clinical response-100 rates in the HMPL-004 and placebo groups were 37.3% and 22% (p=0.087), respectively. The corresponding response-70 and remission rates were 49% and 32% (p=0.061) and 29.4% and 14% (p=0.069), respectively. The mean baseline CRP was 23.5 mg/L in the HMPL-004 group and decreased 11.8 mg/L at week 8 (p=0.004). The mean baseline CRP was 14.2 mg/L in the placebo group and decreased to 10.0 mg/L at week 8 (p=0.008). The mean change in CRP from baseline to week 8 was 11.7 mg/L in the HMPL-004 group and 4.2 mg/L in the placebo group (p=0.068). Thirty-three of 51 (64%) patients in the HMPL-004 group and 28 of 50 (56%) patients in the placebo group reported adverse events (AEs), of which none were considered probably or definitely related to study medication. There was an increase in skin rash and slight increase in bronchitis and urinary tract infections in the HMPL-004 group. Two of 51 (4%) patients in the HMPL-004 group developed serious AEs (SAEs), both were related to CD exacerbation. Four of 50 (8%) patients in the placebo group developed SAEs, 3 were related to CD exacerbation and 1 patient developed lung cancer. Conclusion: Patients with moderately active CD treated with Andrographis Paniculata extract (HMPL-004) 1200 mg/day had numerically greater rates of clinical response -100, response-70 and remission and a numerically greater reduction from baseline in mean CRP concentration as compared with placebo, but these numeric trends did not reach statistical significance. A dose ranging study of HMPL-004 for active ulcerative colitis demonstrated significant efficacy for induction of response, remission, and mucosal healing for an 1800 mg/day dose but not a 1200 mg/day dose. An additional trial to investigate the safety and efficacy of higher doses of HMPL-004 in CD is planned. Disclosure: Dr Sandborn - Consultant: Hutchison MediPharma, Ltd. Dr Targan - Consultant: Hutchison MediPharma, Ltd. Dr Byers - Consultant: Hutchison MediPharma Ltd. Dr Tang - Employee: Hutchison MediPharma Ltd. This research was supported by an industry grant from Hutchison MediPharma Ltd.