Osta is currently focusing on the development of a novel therapeutic for the treatment of Cancer and Alzheimer's Disease. In addition Osta has a rich pipe line of validated targets for the development of novel therapeutics for Osteoporosis and XLH. Osta's strategies for developing new therapeutics for these wide spread diseases that affect a majority of the aging population world-wide are highly original and have little or no precedence in the medical literature. Due to their novel mechanisms of action, the various drugs under development at Osta have the potential to complement current standards of care and satisfy largely unmet medical needs resulting in enhancement of the quality of life of millions of sufferers.

Cancer

Osta is developing novel anti-cancer compounds that target aggressive drug resistant, metastatic and invasive tumors. Osta's scientific team has discovered a novel class of anti-cancer therapeutics that could be used as adjuvant chemotherapeutic agents to treat aggressive, metastatic, invasive and drug resistant tumors.

Osta's anti-cancer compounds are a novel class of cancer drugs that have demonstrated potent anti-tumor activity in a number of drug resistant, aggressive and metastatic human tumor xenograft and orthotopic models and have been found to be well tolerated with no signs of any significant toxicity in mice when given repeatedly via i.p., oral and i.v. routes. Osta's novel compounds have demonstrated strong anti-cancer, anti-metastatic and anti-angiogenic activities.

Osta's anti-cancer compounda are potent and selective HO-1 inhibitors. HO-1, a 32 kDa enzyme is a member of heat shock proteins -HSP32 and catalyzes the conversion of heme, a powerful pro-oxidant into billiverdin, precursor of billirubin, a powerful anti-oxidant. HO-1 is induced in response to oxidative stress and hypoxia in tumors and provides cytoprotection to the tumors by blocking apoptosis and promoting angiogenesis.

Mammalian cells express both HO-1 (heat shock protein 32) and its isoform HO-2. These proteins are sensors and regulators of oxidative stress and tissue redox homeostasis. Under normal physiologic conditions, HO-1 expression is low but can be induced several-fold in response to a wide range of stimuli and activated signaling molecules, including the HO-1 substrate heme, reactive oxygen species (ROS) and nitric oxide species, prostaglandins, cytokines, growth factors such as insulin, and lipopolysaccharide. In contrast to HO-1, HO-2 is constitutively expressed at high levels. HO-1 inducibility is primarily mediated through transcriptional regulation via the presence of diverse responsive elements in the ho-1 gene promoter. HO-1 inducibility can also occur in response to oxidative stress- mediated activation of upstream growth factor receptor signal transduction pathways, including the extracellular signal-regulated kinases ERK1 and ERK2, c-jun-NH2-kinase (JNK), and p38 kinase. These pathways play important roles in the regulation of mitogenesis and cell survival in the face of oxidative damage. Moreover, HO-1 can modulate the activity of cell signaling molecules such as the phosphoinositide 3-kinase, which can be either activated (moderate oxidative stress) to promote oxidative stress- induced cell survival or inhibited (exacerbated oxidative stress) to promote oxidative stress- mediated apoptosis. The classic function of HO-1 is to catalyze heme oxidation to biliverdin, free ferrous iron, and carbon monoxide. Biliverdin is further metabolized to bilirubin through the action of biliverdin reductase. Bilirubin is then oxidized by cytochrome P450 enzymes (e.g., Cyp1A1, Cyp2B1, or Cyp2A5), or glucuronidated by UDPglucuronyl- transferases, and subsequently eliminated as bilirubin glucuronide by the biliary-excretory pathway. These HO-1- mediated byproducts can exert broad physiologic effects in celladaptive response to oxidative stress. For instance, free iron induces the expression of the iron-sequestering protein ferritin and activates Fe-ATPase, an iron transporter that prevents accumulation of intracellular Fe2+. Up-regulation of ferritin and cytosolic iron efflux has a protective effect against oxidative stress. Intracellular carbon monoxide formed through HO-1 catalysis can act as a secondary messenger, which, like nitric oxide, regulates inflammatory signaling. Biliverdin and its by-product bilirubin are antioxidants and prosurvival proteins capable of reducing the inflammatory response and oxidative stress. Therefore, the primary function of HO-1 is to regulate cellular homeostasis and inflammatory response under oxidative stress and to promote cell survival. Moreover, HO-1 can promote angiogenesis through alternative mechanisms, including transcriptional upregulation of vascular endothelial growth factor and production of proangiogenic carbon monoxide.

In tumors, other antioxidative enzymes such as SOD, catalase, glutathione peroxidase are highly down regulated. Therefore, HO system seems to be the major antioxidative system in tumors. Tumors are well known to have high reactive oxygen species (ROS) levels, such as superoxide, lipid peroxyl radicals and peroxynitrite. Moreover, HO-1 is known to up regulate p21. It is also very important to note that CO, a by product of HO-1 catalyzed conversion of heme, is known to inhibit apoptosis, protects against hypoxia, is known to activate p38 mitogen activated protein kinase (MAPK) and inhibits proapoptotic p53.

OB-24, one of Osta's novel HO-1 inhibitors, has been found to greatly potentiate the anti-cancer activity of taxol and completely prevented the formation of both macroscopic and microscopic lymph node metastases in a highly aggressive & metastatic human prostate cancer model, while at the same time, significantly reducing its toxicity.

Inhibition of HO-1 using OB-24 resulted in unprecedented suppression of HRPCA progression and metastasis formation in vivo without overt toxicity and demonstrated a potent synergism with the chemotherapy drug, taxol.

The results obtained to date clearly indicate that OB-24 synergizes with taxol by making this important chemotherapeutic agent significantly more effective and highlight the enormous potential of OB-24 as a highly effective anticancer drug, which either alone or in combination with other chemotherapeutic agents such as taxol, could become an effective new approach for the treatment of metastatic, androgen-refractory and chemotherapy resistant human prostate cancer and other drug resistant, metastatic and aggressive cancers. These results were recently published in the prestigious journal Cancer Research of AACR.

Osta recently announced the results of a pre-clinical efficacy study on a novel anti-cancer therapeutic agent OB-28 in a highly tumorigenic and metastatic human melanoma xenograft mouse model. Data from this pre-clinical study showed statistically significant reduction in the tumor volumes in mice treated with OB-28 compared to mice treated with vehicle alone and the activity of OB-28 was found to be significantly greater than that of Dacarbazine, a chemotherapy drug widely used for the treatment of this type of cancer. OB-28 was found to be well tolerated in mice at various dose levels with multiple administrations. Despite decades of clinical trials on testing various chemotherapy and immunotherapy approaches, a standard first line treatment for metastatic melanoma has yet to be established which has resulted in a very large unmet medical need that Osta plans to address with its novel HO-1 inhibition based therapeutic approach.

Alzheimer's Disease (AD)

Osta is developing a novel small molecule HO-1 inhibitor for the treatment of Alzheimer's disease (AD). The in-vitro and in-vivo data obtained to date strongly supports the hypothesis that the suppression of glial HO-1 hyperactivity may prove to be a rational and effective neurotherapeutic intervention in AD and related neurodegenerative disorders. Osta's lead molecule OB-28 has been shown to significantly ameliorate behavioral anomalies in a transgenic mouse model of AD.

The mechanisms responsible for oxidative damage, pathological brain iron deposition and mitochondrial insufficiency in Alzheimer disease (AD) remain enigmatic. Heme oxygenase-1 (HO-1) is a 32 kDa stress protein that catabolizes heme to biliverdin, free iron and carbon other tissues in various models of disease and trauma. Osta's scientists have demonstrated that 1) HO-1 protein is significantly over-expressed in AD-affected temporal cortex and hippocampus relative to neurohistologically-normal control preparations, 2) in cultured astrocytes, HO-1 up-regulation by transient transfection of the human ho-1 gene, or stimulation of endogenous HO-1 expression by exposure to β-amyloid, TNFα or IL-1β, promotes intracellular oxidative stress, opening of the mitochondrial permeability transition pore and accumulation of nontransferrin iron in the mitochondrial compartment, and 3) the glial iron sequestration renders co-cultured neuron-like PC12 cells prone to oxidative injury. Induction of the astroglial ho-1 gene may constitute a 'common pathway' leading to pathological brain iron deposition, intracellular oxidative damage and bioenergetic failure in AD and other human CNS disorders. These results clearly indicate that inhibiting HO-1 in glia could become an effective new approach for the treatment of AD.

Osteoporosis Therapeutic (OP)

Osta is pursuing the development of a novel anabolic oral drug capable of promoting bone formation. The company has already established proof of validation in-vivo with its lead small molecule OB-14 that has been found to be a potent bone anabolic agent.

Therapeutic Agent for treatment of X-Linked Hypophosphatemic Rickets (XLH)

The Company is developing novel therapeutic agents that could be used to treat XLH.