Santhera Presents New Data on MC-4R Antagonist Program for Treatment of Cancer Cachexia
Liestal, Switzerland, December 7, 2009 - Santhera Pharmaceuticals (SIX: SANN), a Swiss specialty pharmaceutical company focused on orphan neuromuscular diseases, today presented the potential of its oral melanocortin-4 receptor (MC-4R) antagonists for treatment of cancer cachexia at the 5th Cachexia conference in Barcelona, Spain. The Company's latest generation of orally active compounds increased food intake by a factor of 3 to 5 and inhibited the development of cachexia in a disease-relevant animal tumor model. In addition, the preclinical candidate exhibited a significant antidepressant-like effect which is considered relevant since depression is frequent in patients suffering from cancer cachexia. Santhera is in partnering discussions for clinical development and marketing of the MC-4R antagonist program.
The preclinical activity spectrum of Santhera's latest generation of compounds indicate potential effects in all key aspects of cachexia such as lack of appetite, enhanced basic energy expenditure and increased catabolism. The compound presented at the Cachexia conference was shown to have dose-dependent acute positive effects on food intake, i.e. during the first four hours after administration the compound increased food intake 3-5 fold. Moreover, post treatment energy expenditure was significantly decreased in normal mice but not in mice deficient of MC-4R. In a well characterized murine model of cancer cachexia (C26 adenocarcinoma model) daily oral treatment significantly inhibited the development of cachexia and normalized the expression of biochemical markers of muscle wasting. Moreover, the lead compound was shown to exhibit antidepressant-like activity in the rat chronic mild stress model, the most sophisticated rodent model of depression. This effect represents a valuable additional benefit since depression is frequently present in patients suffering from cancer cachexia. Santhera's compounds were found to be orally active and to easily penetrate the blood brain barrier. They were well tolerated in exploratory seven-day tolerability studies in mice and rats and were devoid of undesirable ancillary activities. In addition, the compounds exhibited a clean genotoxicity profile and little liability for drug-drug interactions.
Thomas Meier, Chief Scientific Officer of Santhera, said: "The data strongly support MC-4R antagonists as a promising new therapy option for cancer cachexia, a severe and often deadly metabolic syndrome. The latest generation of our orally bioavailable compounds shows an acute MC-4R mediated increase in food intake and decrease in energy expenditure. Both effects add significantly to the prevention of body weight loss in disease-relevant models and, as a result, qualify MC-4R antagonists as an attractive potential treatment for cancer cachexia and related metabolic syndromes."
About cachexia syndrome and MC-4R antagonists Cachexia (Greek for "poor condition") is one of the most debilitating and life-threatening aspects of cancer and other severe chronic illnesses. The syndrome is associated with anorexia (lack of appetite), fat and muscle tissue wasting, psychological distress and/or depression and a progressively decreasing quality of life. Typically, the involuntary weight loss in excess of 5% in 12 months cannot be compensated for by increased food intake, which results in wasting of both adipose and skeletal muscle tissue and poor physical performance.
The exact nature of the underlying processes remains largely unknown. However, appetite regulating peptides, pro-inflammatory cytokines and other regulatory peptides are considered to be major factors. One pathway by which cytokines can induce anorexia is via an increase of pro-opiomelanocortin gene expression in hypothalamic feeding circuits, leading to an enhanced production of alpha-melanocyte stimulating hormone (alpha-MSH), a strong inhibitor of appetite. The MC-4R in the hypothalamus is a crucial target in the pathway through which alpha-MSH exerts its appetite inhibiting effects. The endogenous antagonist agouti related protein as well as small molecule MC-4R antagonists increase food intake, reduce energy expenditure and catabolic activity. Accordingly, an interruption of this signaling pathway by means of MC-4R antagonists is seen as a promising treatment option for cachexia.
Cancer cachexia affects about one million patients in the North America and Europe. Up to 80% of cancer patients suffer from the syndrome which accounts for approximately 20% of cancer deaths. Despite this high unmet medical need, no effective treatments are available. Currently used pharmacological interventions have limited utility or produce severe side-effects. The potential market size of the cancer cachexia market is estimated to be above USD 1 billion.
References  Weyermann, MC-4R Antagonists, A Potential Treatment For Cachexia. Oral presentation given at the 5th Cachexia Conference in Barcelona, Spain, December 7, 2009.
 Dallmann et al, Right on target: MC-4 receptor mediated increase in food intake and decrease in energy expenditure with an orally bioavailable small molecule antagonist. Poster presented at the 5th Cachexia Conference in Barcelona, Spain, December 5 to 8, 2009.
 Weyermann et al., Efficacy of an orally available selective Melanocortin-4 receptor antagonist in animal models relevant for cancer cachexia. Poster presented at the 5th Cachexia Conference in Barcelona, Spain, December 5 to 8, 2009.
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About Santhera Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of small-molecule pharmaceutical products for the treatment of severe neuromuscular diseases, an area of high unmet medical need which includes many orphan indications with no current therapy. Santhera's first product, Catena® to treat Friedreich's Ataxia, is marketed in Canada and in a well-advanced Phase III development program. The drug is also investigated in a Phase III study in Duchenne Muscular Dystrophy. Commercial rights in Europe for Friedreich's Ataxia and Duchenne Muscular Dystrophy are licensed to Takeda Pharmaceutical. Santhera's second compound JP-1730/fipamezole recently showed efficacy in reducing levodopa-induced Dyskinesia in Parkinson's Disease. Phase III development and commercialization in the United States and Canada are partnered to Biovail. For further information, please visit the Company's web site www.santhera.com.
Catena® is a trademark of Santhera Pharmaceuticals.
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Posted: December 2009