HUMMELSTOWN, PA, United States

Apogee Biotechnology Corporation

www.apogee-biotech.com
HUMMELSTOWN, PA, United States
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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase II | Award Amount: 1.14M | Year: 2014

DESCRIPTION provided by applicant Diffuse large B cell lymphoma DLBCL represents one of the most common variants of Non Hodgkinandapos s lymphoma NHL and oncogenic herpesviruses EBV and KSHV are the etiologic agents for the majority of these tumors in patients over or those infected with the human immunodeficiency virus HIV Despite modest improvements in outcomes for patients receiving standard therapy patients with virus associated DLBCLs exhibit more widespread andquot extranodalandquot disease and less favorable outcomes Notably increased treatment failure and mortality have been observed for patients from urban minority predominant cohorts with high rates of virus associated DLBCL and HIV infection who have been largely excluded from clinical trials Apogee Biotechnology Corporation has developed the first non lipid inhibitors of sphingosine kinase SK and has evaluated their biologic and therapeutic activity in a variety of models for cancer and inflammatory diseases The first clinical compound in this series ABC is an orally available selective inhibitor o SK that attenuates signal transduction induces tumor cell death and inhibits host angiogenesis and inflammation in the context of solid tumor formation We have found that ABC induces apoptosis for virus infected DLBCL lines in part through attenuation of virus associated signal transduction Most importantly ABC significantly reduces virus associated DLBCL tumor burden in xenograft models for both EBV and KSHV DLBCLs Therefore we hypothesize that ABC will have significant clinical activity for many DLBCLs refractory to standard therapy especially virus associated DLBCLs To begin development of ABC as a new drug for DLBCL we propose to conduct a Phase I IIa clinical study of this agent enrolling patients with refractory relapsed DLBCL from minority predominant urban populations in Louisiana at high risk for poor outcomes with this disease In this open label dose escalation study ABC will be given orally to HIVneg or HIV patients with primary objectives including determination of the maximum tolerated dose MTD dose limiting toxicities and pharmacokinetics for ABC in these patients Secondary objectives will include determination of the effects of ABC on plasma sphingosine phosphate levels PBMC and tumor associated viral load EBV and KSHV and tumor expression of S P receptors as first steps toward identification of putative biomarkers for drug resistance We will also evaluate antitumor activity for ABC using objective radiographic and clinical assessments Up to patients will be enrolled in the dose escalation phase of the study and once the MTD has been established up to additional patients with DLBCL will be enrolled using this dose in order to obtain additional preliminary efficacy and safety data This study will form the foundation for follow on clinical trials of ABC in patients with DLBCL thereby expanding the commercial market for this agent to include hematologic malignancies and offering a new therapeutic approach for underrepresented patients for whom DLBCL incurs especially high mortality PUBLIC HEALTH RELEVANCE DLBCL incurs high mortality for patients with advanced or refractory disease so new drugs that target critical pathways controlling growth and survival of DLBCL cells are desperately needed Sphingolipid metabolism and sphingosine kinases in particular may play a critical role in DLBCL progression ABC is a novel sphingosine kinase inhibitor that has anti DLBCL activity in mouse models as a single agent and can be used alone or in combination with standard drugs given to DLBCL patients to reduce tumor growth The proposed Phase I IIa clinical trial will establish the maximum tolerated dose safety profile and preliminary efficacy for ABC in patients from an underrepresented minority predominant cohort with treatment refractory DLBCL for whom the disease incurs especially high mortality


Patent
Apogee Biotechnology Corporation | Date: 2010-03-12

The invention relates to prodrugs of hydroxyl-substituted adamantane compounds, pharmaceutical compositions thereof, and methods for inhibiting sphingosine kinase and for treating or preventing hyperproliferative disease, inflammatory disease, or angiogenic disease.


Patent
Apogee Biotechnology Corporation | Date: 2011-10-19

The invention relates to substituted adamantane compounds, pharmaceutical compositions thereof, processes for their preparation, and methods for inhibiting sphingosine kinase and for treating or preventing hyperproliferative disease, inflammatory disease, or angiogenic disease.


Patent
Musc Foundation For Research Development and Apogee Biotechnology Corporation | Date: 2010-05-10

Ischemia-reperfusion injury remains a primary cause of morbidity and mortality in individuals who experience disruption of normal blood flow to one or more major organs. For example, there are no clinically proven strategies that prevent acute renal failure following cardiac surgery. The present invention provides a variety of methods for the treatment or prevention of ischemia-reperfusion injury. In one aspect of the invention, a method for treating or preventing ischemia-reperfusion injury includes administering to a subject an effective amount of a sphingosine kinase inhibitor. Sphingosine kinase inhibitors are very effective in the protection against IR-induced acute renal failure and liver failure. Moreover, the effects occur very early after administration, requiring only a very short time of treatment. Toxicology studies with sphingosine kinase inhibitors demonstrate that they have low toxicity, even in long-term treatment.


Patent
Apogee Biotechnology Corporation | Date: 2011-04-27

The invention relates to substituted adamantane compounds, pharmaceutical compositions thereof, processes for their preparation, and methods for inhibiting sphingosine kinase and for treating or preventing hyperproliferative disease, inflammatory disease, or angiogenic disease.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 316.92K | Year: 2012

DESCRIPTION (provided by applicant): The goal of this program is to develop novel inhibitors of human neutral ceramidase (ASAH2) that are effective as therapeutic agents for Inflammatory Bowel Diseases (IBDs). Sphingolipids are being increasingly recognized as key mediators of inflammation, and are known to mediate the effects of pro-inflammatory cytokines such as tumor necrosis factor-? (TNF?) that are of central importance in IBD. Accumulating evidence demonstrates that sphingosine-1-phosphate (S1P) produced by the combined action of sphingomyelinases, neutral ceramidase and sphingosine kinases within gastrointestinal epithelial and endothelial cells drives the inflammation processes in IBD. Therefore, sphingolipid metabolizing enzymes are potential molecular targets for the development of new drugs for the treatment of IBDs. Because of the pivotal role of ceramidases in regulating inflammation, Apogee Biotechnology Corporation is developing ceramidase inhibitors to treat inflammatory diseases. We have identified the first non-lipid, i.e. drug-like , inhibitors of human ASAH2, which is the dominant ceramidase isozyme expressed in the human gastrointestinal tract. In this Phase 1 SBIR project, we will evaluate the pharmacology and anti-IBD activity of three novel ceramidase inhibitors (representing three chemotypes of ceramidase inhibitors currently being optimized) in two in vivo models of IBD through the following Specific Aims: 1. To synthesize and evaluate the toxicity and pharmacokinetics of novel ceramidase inhibitors. We have identified three chemotypes of drug-like ceramidase inhibitors by high-throughput screening and medicinal chemistry. The lead compound within each of these chemotypes will be synthesized in gram quantities for in vivo testing.The Maximum Tolerated Dose and pharmacokinetics of each of these ceramidse inhibitors will be determined to optimize treatment protocols in the IBD models. 2. To evaluate the therapeutic efficacies of ceramidase inhibitors in the DSS model of ulcerative colitis. Each of the novel ceramidase inhibitors will be tested for efficacy in the dextran sulfate sodium (DSS) model of ulcerative colitis in mice, using a combination of clinical, morphological and biochemical endpoints. 3. To evaluate the therapeutic efficacies of ceramidase inhibitors in the TNBS model of Crohn's Disease. The efficacies of the three novel ceramidase inhibitors will be examined in the TNBS model of Crohn's disease in mice, utilizing similar evaluation endpoints as in Aim 2. This work will provide the first proof-of-principle efficacy studies of ceramidase inhibitors in widely- utilized models of IBD. We have extensive experience with the proposed IBD models and a proven track record for bringing sphingolipid-targeted drugs into clinicaltrials. We believe that the use of neutral ceramidase inhibitors for te treatment of IBD is an innovative approach that is likely to be rapidly translated to the clinic. PUBLIC HEALTH RELEVANCE: According to the Centers for Disease Control and Prevention, the estimated incidence of IBD in the US is 1.4 million persons, with an overall health care cost of more than 1.7 billion. This chronic condition is without a medical cure and commonly requires a lifetime of care. Over the long term, up to 75%of patients with Crohn's disease and 25% of those with ulcerative colitis will require surgery, making it clear that new therapeutic approaches are needed. Extensive work, including our Preliminary Studies, suggests that inhibition of neutral ceramidase may provide a new therapy for these diseases. The proposed studies will provide the first test of this hypothesis.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.33M | Year: 2015

DESCRIPTION provided by applicant Multiple myeloma MM is the second most common hematological malignancy in the United States and remains an incurable disease since nearly all MM patients will eventually relapse and develop resistance to currently available drugs Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor biology In particular sphingosine kinases SK and SK provide a potential site for manipulation of the ceramide sphingosine phosphate S P rheostat that regulates the balance between tumor cell proliferation and apoptosis as well as tumor sensitivity to drugs and radiation We have recently demonstrated that SK is overexpressed in MM and that inhibition of SK in MM cell lines by ABC down regulates c Myc expression and promotes apoptosis in MM cells Importantly ABC also effectively inhibits tumor growth in vivo in myeloma xenograft models ABC has recently completed phase I testing in patients with advanced solid tumors and we hypothesize that this drug will be useful for the treatment of MM patients In this phase SBIR project we will conduct the following Specific Aims Perform a phase Ib clinical trial to determine the safety pharmacokinetics and pharmacodynamics of ABC when combined with dexamethasone in relapsed refractory MM patients We will perform a phase b trial with up to patients to determine the safety maximal tolerated dose MTD pharmacokinetics and pharmacodynamics of ABC combined with dexamethasone in relapsed and or refractory MM patients who have previously been treated with both a proteasome inhibitor and an immunomodulatory agent and Perform a phase II clinical trial to determine the preliminary efficacy of ABC combined with dexamethasone in relapsed refractory MM patients Once the MTD has been established up to additional patients with refractory relapsed MM will be enrolled at the MTD to confirm safety and to investigate preliminary efficacy in this population We expect that this clinical trial will have important implications in the treatment of MM We believe that the proposed studies constitute a focused approach for developing a novel treatment for patients with MM a disease with a high unmet clinical need If positive these data will provide justification for a larger multi center phase III study PUBLIC HEALTH RELEVANCE Multiple myeloma MM is a common but incurable disease that requires new therapies Sphingolipid metabolism is being increasingly recognized as a key pathway in cancer biology and is changed in MM cells We have developed the first clinical drug that inhibits a key enzyme SK and have extensive preclinical data that suggest it will be active against MM This project will extend the clinical testing of this drug into MM patients to assess its safety and to provide a preliminary estimation of its therapeutic potential Successful completion of these studies could have important implications for the treatment of MM


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant Prostate cancer PCa is the most commonly diagnosed non cutaneous malignancy and the second leading cause of cancer related deaths in US males PCa at all stages is dependent on the activity of the androgen receptor AR and consequently targeting this pathway has been a focus for therapeutic intervention Additionally Myc is one of a few bonafide oncogenes imperative to PCa progression and aggressiveness which is often deregulated through the disease course and represents a potential but currently undruggable target for PCa Radiation therapy often combined with androgen deprivation therapy ADT is standard of care for patients presenting with organ confined or locally advanced disease and has recently been approved for treatment of metastatic disease Deregulation of AR and Myc are both implicated in decreased sensitivity to radiotherapy Therefore novel therapies that inhibit AR and or Myc signaling could effectively radiosensitize PCa cells thereby improving disease management It is well established that sphingolipid metabolism plays key roles in tumor biology In particular sphingosine kinases SK and SK are a potential site for manipulation of the ceramide sphingosine phosphate rheostat that regulates the balance between tumor cell proliferation and apoptosis as well as tumor sensitivity to radiation We and others have demonstrated that SKs are frequently overexpressed in many human cancers including PCa and that inhibition of SK activity has anti proliferative effects on tumor cells Apogee Biotechnology Corporation has identified orally available SK inhibitors with activity in vitro and in vivo The lead SK inhibitor designated as ABC has antitumor and anti inflammatory activities in several in vivo models while exhibiting minimal toxicity ABC has recently completed phase I clinical testing in patients with advanced solid tumors but has not been previously assessed in PCa patients or preclinical models We have now found that ABC effectively decreases AR and Myc expression and activity attenuates PCa cell growth and inhibits in vivo tumor growth Therefore we hypothesize that ABC can radiosensitize PCa in vitro and in vivo and significantly diminish tumor growth To support expanding clinical trials of ABC into PCa patients we will conduct studies to determine the therapeutic efficacy of ABC in in vitro and in vivo models of PCa in combination with a relevant radiotherapy regimen The following Specific Aims will be addressed in this phase SBIR project To analyze the in vitro capability of ABC to sensitize PCa cells to radiation therapy To determine the mechanism for ABC mediated radiosensitization and To evaluate the ability of ABC to modify radiation therapy for PCa in vivo Clear mechanistic rationale and extensive Preliminary Studies support the hypothesis that ABC will provide a new effective therapy for PCa that uniquely targets multiple pathways driving disease aggressiveness progression and resistance to therapy Successful completion of this project will leverage our clinical experience with ABC by providing justification to the FDA to expand our clinical trials into PCa a disease with a high unmet clinical need PUBLIC HEALTH RELEVANCE Radiation therapy is a common treatment for prostate cancer however a significant percentage of patients do not respond or develop radioresistance New drugs targeting critical pathways that drive growth and survival of prostate cancer cells in response to radiation are desperately needed Sphingolipid metabolism and sphingosine kinases in particular may play critical roles in prostate cancer We have identified a novel sphingosine kinase inhibitor that simultaneously inhibits three key pathways that promote resistance to PCa radiation therapy Here we will determine the effectiveness of this inhibitor in prostate cancer models with the goal to identify new strategies for the treatment of this disease


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.12K | Year: 2014

DESCRIPTION (provided by applicant): Mucositis caused by excessive inflammation within the gastrointestinal tract is a costly and debilitating toxicity commonly experienced by patients receiving radiation and/or drugs as cancer therapy. Sphingolipids are being increasingly recognized as key mediators of inflammation, and are known to be essential for signaling by pro-inflammatory cytokines such as tumor necrosis factor-?(TNF?) and IL-4 that are of central importance in mucositis. In particular, sphingosine1-phosphate (S1P) within gastrointestinal cells generated in response to many common anticancer drugs is critical for the recruitment and activation of neutrophils that escalate inflammatory processes in mucositis. Therefore, disruption of chemotherapy-induced S1P production is a new targeted approach to the prevention and/or treatment of mucositis. Because of the pivotal roles of sphingosine kinases (SKs) in regulating inflammation and tumor growth, Apogee Biotechnology Corporation is developing SK inhibit


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 593.45K | Year: 2013

DESCRIPTION (provided by applicant): Radiation-induced production of pro-inflammatory and pro-fibrotic cytokines results in chronic and irreversible damage to the lungs. To date, no agent has demonstrated a sufficient safety profile to be utilized as a clinical drug for mitigating damage from exposure to radiation from accidental or terroristic nuclear events. Consequently, there is a great need for new, mechanistically-targeted drugs that can be utilized to mitigate radiation poisoning of humans following unintended exposure. Many studies have implicated sphingolipid metabolism as a critical mediator of inflammatory and fibrotic processes. Inflammatory and pro-fibrotic cytokines produced by radiation exposure (e.g. TNF and TGF ) activate sphingomyelinases and ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1P). It is established that SK activation and production of S1P are essential for signaling responses to inflammatory cytokines, including their ability to induce adhesion molecule expression via activation of NF?B. Similarly, collagen synthesis in response to TGF is dependent on S1P production by SKs. Therefore, SKs are rational new targets for drugs that attenuate damaging inflammation and fibrosis. Apogee Biotechnology Corporation has identified the first orally-available SK inhibitors with activity in vitro and in vivo. The lead SK2 inhibitor, designated as ABC294640, has antitumor and anti-inflammatory activitiesin several in vivo models, while exhibiting very low toxicity to the animal. Our Preliminary Studies indicate that treatment of mice with ABC294640 protects against toxicity from total body or abdominal irradiation when the compound is given either pre-exposure or post-exposure. We hypothesize that suppression of SK2 activity by ABC294640 will mitigate pulmonary fibrotic damage from exposure to ionizing radiation. To establish justification for moving ABC294640 toward clinical trials for radiomitigation,we will conduct the following Specific Aims: 1) To determine the mechanism for ABC294640 protection against cytokine-induced fibrotic responses in cultured human fibroblasts; and 2) To characterize the ability of ABC294640 to protect against pulmonary fibrosis from thoracic irradiation. These studies will provide the experimental validation needed to justify future confirmatory studies in non- human primates, and ultimately clinical trials in humans. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Exposure to ionizing radiation, which can occur through accidental or terroristic nuclear events, causes damage to a variety of organs including the lungs because of chronic inflammation and fibrosis. We have developed an orally-available inhibitor ofthe enzyme sphingosine kinase-2 that has anti-inflammatory activity in several animal models. We will examine the effects of this compound in mice to determine its ability to reduce radiation-induced lung damage.

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