Glenmark Pharmaceuticals announced that its Novel Chemical Entity (NCE) “Revamilast” (GRC 4039) has initiated phase II b human dose range finding trials globally. Revamilast is an orally active, potent and selective inhibitor of phosphodiesterase 4 (PDE 4) that is currently being developed by Glenmark for the treatment of chronic inflammatory disorders such as asthma, Rheumatoid Arthritis (RA) and other inflammatory diseases. The phase II b studies that will be carried out will help establish the efficacy and safety of the molecule and will also provide dose range finding data for Revamilast.

Dr Steffen Stuerzebecher, president and chief medical officer, Glenmark Pharmaceuticals Ltd said, “The clinical trials and the animal studies data for Revamilast are promising for both indications i.e. asthma and RA. There is a huge unmet need for both these chronic medical conditions globally. For Glenmark, this is a significant development as we have built on more than a decade of experience in the PDE 4 space to progress an exciting molecule to phase II human trials.”

In phase I studies carried out mainly in the United Kingdom, nearly 150 healthy volunteers have been dosed and no Serious Adverse Events (SAE) have been noted. The pharmacodynamic evaluation in healthy human volunteers treated with Revamilast suggests a good ex-vivo inhibition of the inflammatory marker TNF-a with maximum inhibition upto 93 per cent. Based on these results and animal model data, it is expected that Revamilast would be beneficial in a variety of inflammatory disorders. Additionally, Revamilast does not appear to be metabolized to carcinogenic metabolites (ADCP N-oxide and ADCP N-oxide epoxide); and plasma samples from a phase I study analysed for such metabolites of Revamilast, showed no levels were detected in human plasma.

With the completion of several phase I studies, Glenmark has initiated a global phase II b trial for Revamilast in patients with asthma. Glenmark has already received approval from respective authorities in the UK, Poland, India and Czech Republic to conduct phase II b studies. Regulatory submissions have also been completed in Russia. The primary objective of this 12-week, double blind, placebo controlled, dose range finding study is to evaluate the effects of Revamilast at three doses on lung function (FEV1) in nearly 450 patients with chronic persistent asthma.

Glenmark has also initiated another global phase II b trial with Revamilast in patients with RA. Glenmark has already received approval from the MHRA, UK, India, Poland and the Philippines to conduct phase II b studies for RA. Regulatory submissions have also been completed in Sri Lanka. The objective is to determine the efficacy of three doses of Revamilast compared to placebo in the treatment of more than 400 patients with active RA who showed an inadequate response to methotrexate.

In parallel to these two clinical studies, Glenmark is also conducting various other clinical and non-clinical studies to ensure timely entry into phase III trials. Glenmark intends to initiate phase III trials for at least one indication in the second half of FY 2012-13.

PDE 4 inhibitors represent class of therapeutic agents with a unique mechanism of action for the treatment of a range of chronic inflammatory disorders including COPD, asthma, RA, IBD and psoriasis. This mechanism of action of PDE4 inhibitors would be useful in treating chronic inflammatory conditions such as RA and asthma. Many manifestations of RA are significantly influenced by the effects of pro-inflammatory cytokines (e.g., TNF, IL-1, IL-6). In asthma, there remains a need for the development of novel anti-inflammatory therapies that are at least equally effective and possess a superior safety profile in comparison to corticosteroids.

PDE 4 inhibitors relax smooth muscles and attenuate the inflammatory response to a wide variety of stimuli and in particular suppress many cytokines, including TNF-a production in mononuclear cells. Therefore, PDE 4 inhibitors present a novel treatment opportunity for a range of chronic inflammatory diseases. A first-in-class PDE 4 inhibitor, Roflumilast, has recently been approved in the European Union and in Mar’2011, Forest Laboratories Inc. and Nycomed A/S have received US FDA approval for Roflumilast to treat symptoms associated with severe Chronic Obstructive Pulmonary Disease (COPD).