Optimal dose finding for novel antimalarial combination therapy.

A recent discussion meeting convened by the Medicines for Malaria Venture examined how best to manage the discovery and preclinical pipeline to achieve novel combination therapies which would address the key clinical needs in malaria. It became clear that dose optimisation of components within combination therapy was a key issue in achieving antimalarial efficacy and for preserving that efficacy against parasite resistance emergence. This paper outlines some of the specific issues in malaria that cause dose-ranging and dose-optimisation studies to be particularly challenging and discusses the potential of factorial study design to address such challenges.

Treatment of active Crohn's disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study.

BACKGROUND: Monoclonal antibodies to the pro-inflammatory cytokine tumour necrosis factor-alpha have shown efficacy in treating Crohn's disease, but can be immunogenic. Soluble tumour necrosis factor-binding proteins are being studied as potential alternative anti-tumour necrosis factor agents in Crohn's disease. AIM: To investigate the safety and efficacy of onercept, a recombinant form of the natural human soluble p55 tumour necrosis factor receptor, in the treatment of patients with active Crohn's disease. METHODS: In a pilot study, 12 patients with active Crohn's disease were randomized to receive onercept at either 11.7 or 50 mg three times weekly for 2 weeks. Patients were followed up for 6 months after the end of treatment. RESULTS: The Crohn's disease activity index decreased rapidly during treatment in both groups. Seven responses (Crohn's disease activity index decrease of 100 points) were observed over the first 6 weeks of the study, including five remissions (Crohn's disease activity index decrease of 150 points). Improvement was sustained for 2-4 months after stopping treatment. Treatment was well tolerated. No patients developed antibodies to onercept. CONCLUSIONS: Neutralizing the activity of tumour necrosis factor-alpha with its soluble p55 receptor may be valuable in the treatment of patients with Crohn's disease. Larger placebo-controlled trials are indicated.