Lodotra^™

In a number of diseases involving chronic inflammation and pain, such as rheumatoid arthritis (RA), severe asthma and polymyalgia rheumatica (PMR), symptoms are linked to sufferers’ abnormal circadian fluctuations in pro-inflammatory cytokines. For example, a nocturnal rise in pro-inflammatory cytokine levels is responsible for the morning stiffness associated with RA, one of the most disabling symptoms of the disease.

Lodotra^™ is a circadian cytokine modulator (CCM) based on a night-time release formulation of prednisone, a proven and effective compound for the treatment of RA, severe asthma and PMR, which is safe at low doses. By synchronizing prednisone delivery time with the sufferer’s elevated cytokine rhythm, Lodotra^™ takes effect at a physiologically optimal point to inhibit cytokine production and thus significantly reduce symptoms.

Prednisone belongs to a therapeutic class known as glucocorticoids. Glucocorticoids are used to suppress various autoimmune, inflammatory and allergic disorders by inhibiting the production of various pro-inflammatory cytokines. Glucocorticoids bind to a well-characterized intercellular receptor known as the glucocorticoid receptor. Upon binding of the glucocorticoid to the receptor, this complex binds to specific DNA sequences and blocks the transcription of genes that encode for various pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α).

Lodotra^™ takes the form of a specially formulated tablet using a delayed release technology which, once ingested, does not release the prednisone until approximately four hours later. Maximum plasma levels are reached six hours after intake. This way, a patient can swallow the tablet at 10pm before going to sleep and the dose of prednisone will not be released until 2am and will reach maximum plasma levels at 4am; the optimal timing to relieve the stiffness and pain on waking. This night time release formulation is especially suited to the treatment of inflammatory diseases that show marked circadian cytokine variations leading to worsening symptoms at night or in early morning.

Lodotra^™ successfully completed a European Phase 3 trial in RA in 2006 when a dossier was submitted to 15 European countries using the decentralized procedure. After successful completion the marketing authorization in these countries is expected in the second half of 2008. A second pivotal phase 3 trial is ongoing in preparation for the filing of a NDA with the FDA seeking US approval of Lodotra^™ for the treatment of the signs and symptoms of RA including morning stiffness. Lodotra^™ is also being developed for the treatment of severe asthma and polymyalgia rheumatica (PMR). Results from the clinical trials that Lodotra^™ has undergone can be found here.