MT-102 was selected as our lead compound using a large scale screening study to investigate the performance of potential compounds in a preclinical model of cancer cachexia. In this study, MT-102 demonstrated superior efficacy relative to other tested agents, including agents in advanced stages of clinical development for cachexia. In this model, MT-102 not only significantly improved body weight, muscle mass and fat mass, but it also significantly improved mobility and survival.
This surprising level of activity can be explained by the unique dual mode of action of MT-102, which has both anti-catabolic and pro-anabolic activity. This Anabolic Catabolic Transforming Agent (ACTA) thus directly impacts two of the principle pathophysiological hallmarks of cachexia and is a very promising mode of treatment.
MT-102 has completed two clinical studies, where the product was administered orally to 132 subjects with little difference in adverse event profiles between MT-102 and placebo.
PsiOxus Therapeutics has now initiated a multinational randomised double blind placebo controlled phase II clinical study, which will be reported in 2011. This clinical proof of concept study will examine the impact of MT-102 on weight change, body composition, physical performance and survival.
In addition to cachexia, MT102 has been shown to have beneficial effects upon sarcopenia in vivo. This represents the second indication for MT-102, and this will be investigated in future clinical studies.
Cachexia
Cachexia is a wasting disease, which accompanies a wide range of serious illnesses including cancer, heart failure, COPD, renal failure, cirrhosis and rheumatoid arthritis and that is associated with significant morbidity and mortality. The clinical hall mark of cachexia is unintended weight loss. Cachexia was clinically defined by the Cachexia Consensus Group, at a meeting co-chaired by [Professor Anker] in 2008, as an involuntary weight loss of at least 5% of weight in 12 months or less, in the presence of underlying disease and present with signs and symptoms of muscle weakness and fatigue [1].
The word cachexia originates from the greek kakos meaning bad and hexis meaning condition, a term that clearly articulates its association with very poor outcomes. Described as a disease by Hippocrates as early as the sixth century BC the adverse impact of weight loss on survival has always been well known, "...the shoulders, clavicles, chest and thighs melt away. This illness is always fatal. . ." (Hippocrates 460-370 BC). Indeed, today we know that cachexia is a powerful risk factor for increased morbidity and mortality independent of the underlying condition. The US National Cancer Institute estimates cachexia to be the immediate cause of death in 20% to 40% of cancer patients [2]; in gastrointestinal tract cancers the proportion is 30-50%, rising up to 80% of deaths in patients with advanced pancreatic cancer [3]. In fact, despite the current obsession with obesity as a risk factor, a low body mass index is at least as important in predicting excess mortality as a high body mass index, even in the absence of disease [4]. This effect becomes more pronounced with age [5] and chronic disease [6] with the result that only a low BMI has a consistent correlation with mortality across both healthy and chronically ill populations. Cachexia thus strongly deserves direct medical attention. However, by definition, dietary measures alone are not sufficient to treat cachexia. Despite this fact, nutritional support is frequently the only course left for treating physicians to follow. Further research and development, and ultimately new forms of treatment are thus urgently required.
From a pathophysiological viewpoint, cachexia can be considered to be the result of a complex interaction of many pathways initiated by one or more chronic disease. These changes include the chronic hyperactivation of several neuro-endocrine systems , systemic inflammation, hormone resistance and free radical generation. The end result is a progressive and sustained increase in catabolism (tissue breakdown) coupled to impaired anabolism (tissue build-up). This catabolic / anabolic imbalance results in cell death and tissue wasting leading to a progressive cycle of global weight loss, weakness and fatigue. Understanding and then breaking or reversing this catastrophic cycle will be critical for generating successful therapies.
The activity of most research groups has focused upon pro-anabolic treatments including growth hormones, ghrelins, specific androgen receptor modulating steroids (SARMS) and myostatin inhibitors. PsiOxus has focused our approach on anti-catabolic approaches and our lead compound, MT-102 has both anti-catabolic and pro-anabolic activity. MT-102 is thus referred to as a Anabolic Catabolic Transforming Agent and operates on both of the fundamental mechanisms using a single agent.
Sarcopenia
Sarcopenia is the loss of muscle mass and strength associated with ageing [8]. Although it shares many similarities with cachexia, there are also certain differences. The prevalence of sarcopenia for those over 64 years of age has been shown to be 22.6% in women and 26.8% in men, rising to 31.0% and 52.9% respectively in those over 80 years of age [9]. It can thus be estimated that over 3% of the total world population will be affected by sarcopenia by 2015. Currently there are no registered treatments for sarcopenia.
Sarcopenia is a word coined from Greek by Irwin Rosenberg in 1988: sarx means flesh and penia means loss. The Framingham Disability Study found that the ability to perform heavy household work, walk one half mile, and climb stairs declined with age and that participants aged 75-84 were more likely to require help with activities of daily living.
Market potential and current treatment
Cachexia is currently estimated to afflict at least 1% of the population, equating to 4.75 million people in the EU, 3 million in the USA and 1.25 million in Japan. The unmet medical need is thus highly significant and the potential accessible market can be conservatively estimated to exceed US$4 billion.
It has been estimated that over 3% of the total world population will be affected by sarcopenia by 2015. Currently there are no registered treatments for sarcopenia. The projected market size has sometimes been estimated to be similar to that of osteoporosis.
Until recently, little research attention has been given to cachexia and sarcopenia as opposed to the underlying illnesses that predispose patients to the syndrome.There are currently no widely approved agents for either Cachexia or Sarcopenia.
Therapeutic options are thus relatively sparse despite the very large market opportunity. However, a great deal of international activity is ongoing in academia, biotech companies and large multinational pharmaceutical companies. Most research activity has focused upon pro-anabolic treatments including growth hormones, ghrelins, specific androgen receptor modulating steroids (SARMS) and myostatin inhibitors. PsiOxus has focused our approach on anti-catabolic approaches and our lead compound, MT-102 has both anti-catabolic and pro-anabolic activity. MT-102 is thus referred to as a Anabolic Catabolic Transforming Agent.
