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BOSTON, MA, United States

Arisaph Pharmaceuticals, Inc. | Date: 2010-12-03

Pharmacological preparations and substances for the treatment of diabetes, cancer, and atherosclerosis.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 498.79K | Year: 2015

DESCRIPTION provided by applicant Nonalcoholic steatohepatitis NASH characterized by liver steatosis with hepatocellular injury and inflammation is a potentially serious condition with up to of patients progressing to cirrhosis with complications of portal hypertension liver failure and hepatocellular carcinoma NASH is highly prevalent in patients with type diabetes T D and is an escalating health problem due to the global epidemic of T D Currently control of lipids by diet and exercise is the only approved treatment but long term effectiveness is questionable because many patients are unable to comply with the required dietary and lifestyle changes emphasizing the need for an effective pharmacotherapeutic approach The thiazolidines and vitamin E can improve liver histology in NASH patients but they are handicapped by formidable adverse effects The investigational agent obeticholic acid has been shown to improve the biochemical and histological features of NASH but drug safety requires further evaluation in the light of potentially adverse effects on blood lipids A new compound ARI MO can reverse the elevation of the enzyme markers of liver damage in hyperlipidemic hamsters and reduce circulating triglycerides and body weight ARI MO is a synthetic analog of nicotinic acid NA which itself has been reported to reverse hepatic steatosis in a hyperlipidemic model NA significantly reduced liver lipid in a small clinical trial but clinical acceptance in NAFLD NASH patients is unlikely given its association with hepatoxicity impaired insulin sensitivity and flushing ARI MO does not interact with the high affinity receptor for NA GPR A which mediates the latter two adverse effects but preclinically and clinically ARI MO retained beneficial effects on lipid levels and inflammation ARI MO did not impair glucose control cause flushing or show any signs of hepatotoxicity in human phase I trials suggesting feasibility as a drug candidate in NAFLD NASH The next step is to examine efficacy in NAFLD NASH patients with moderate biopsy proven steatohepatitis in a month study The Specific Aim is to demonstrate that ARI MO reduces intrahepatic lipid content and improves liver function via beneficial changes in liver function tests In order to advance into a placebo controlled proof of concept phase II clinical study in NASH patients SBIR phase ARI MO must meet specific Benchmarks at least a reduction in intrahepatic lipid content measured by MRI spectroscopy and a or greater reduction in the alanine transaminase marker of liver disease A study director at an advanced clinical site Beth Israel Deaconess Medical Center a homogeneous study population selected by liver histology indicative of reversible disease and the safety profile of ARI MO provide confidence that the study can be successfully executed to yield definitive measurable outcomes PUBLIC HEALTH RELEVANCE Nonalcoholic steatohepatitis NASH is an escalating public health problem linked to the global diabetes epidemic and is characterized by liver steatosis accompanied by hepatocellular injury inflammation and risk of progression to cirrhosis with complications of portal hypertension liver failure and hepatocellular carcinoma Effectiveness of diet and exercise to control NASH is limited by patient compliance moreover existing therapeutic agents such as the thiazolidines and vitamin E and an otherwise promising investigational agent obeticholic acid are handicapped by significant safety concerns Efficacy of the new investigational agent ARI MO will be tested in NAFLD NASH patients in a trial with intrahepatic lipid and liver enzyme endpoints

Arisaph Pharmaceuticals, Inc. | Date: 2014-05-12

Pharmacological preparations and substances for the treatment of diabetes, cancer, and atherosclerosis.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 232.85K | Year: 2013

DESCRIPTION (provided by applicant): In the United States, around 76,250 new cases of melanoma and 9,180 melanoma-related deaths are predicted for 2012. With the therapeutic options currently available, metastatic melanoma patients face the bleak prospectof at best, 10 month's survival and a one-in-ten chance of surviving for 10 years. Surgery and radiation therapy are the mainstay of treatment. Dacarbazine-based chemotherapy remains after 30 years, for want of anything better, to be the main systemic therapy. As currently used, immunotherapy affords little improvement. High dose IL-2 (Proleukin) and ipilimumab (Yervoy) can increase survival, but only in a few patients, and at the risk of severe toxicity. Mutations in the BRAF oncogene occur in 80% of melanomas and activate the B-Raf serine/threonine kinase to drive uncontrolled cell growth. The new, targeted agent, vemurafenib (PLX4032), inhibits B-Raf activated by the V600E mutation occurring in 85% of BRAF mutations in melanoma. High response rates, benign and manageable toxicities, and the availability of a companion diagnostic for the BRAFV600E mutation raised the prospect of a cure in metastatic melanoma. This hope has been thwarted by the development of drug resistance and the recurrence of malignantdisease only months after regression in response to PLX4032. The period of remission produced by PLX4032 provides a window of opportunity for immunotherapeutic approaches that might activate tumor immunity to suppress the recurrence of PLX4032-resistant melanoma. Arisaph has identified a small molecule inhibitor of the prolyl peptidase family, ARI-4175, that can activate tumor immunity to kill tumors via the induction of immunoregulatory cytokines and chemokines. Arisaph has selected ARI-417 as a second-generation drug candidate with greater activity and less toxicity than the related compound, PT-100 (talabostat). ARI-4175 is remarkably effective in producing immune rejection of tumors in mice. Therefore, if given during the period of remission produced byPLX4032, ARI-4175 might activate an immune response that can suppress reemergence of disease. This hypothesis will be tested with the Specific Aim of demonstrating that ARI-4175 can inhibit progression of tumors after the initial response to PLX4032 in a model of BRAFV600E-positive melanoma established by Dr. Philip Hinds (Tufts Medical Center). In order to be a viable drug candidate, ARI-4175 must produce a significantly greater antitumor effect than PLX4032 alone by the activation of tumor immunity afterPLX4032 treatment in BRAFV600E-positive melanoma in mice. If ARI-4175 meets the test of feasibility in STTR Phase I, IND-enabling studies and initiation of clinical trials to investigae safety and efficacy will be proposed for Phase II. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Metastatic melanoma is a lethal skin cancer with response rates to chemotherapy of only 5-20%, and although immunotherapy (Proleukin and Yervoy) provides an alternative option that can produce durable responses andlong-term survival, as currently used, immunotherapy only provides a benefit in a small proportion of patients. A newer targeted agent, vemurafenib (PLX4032), is a B-Raf kinase inhibitor that can produce remarkable responses in melanoma harboring the BRAFV600E mutation, but following the initial response, drug resistance allows the recurrence of aggressive malignant disease after only a few months. This proposal will test the feasibility of using a small molecule immunotherapeutic agent to activate a tumor-specific immune response that can suppress the recurrence of disease after the initial regression of melanoma lesions in response to PLX4032.

Trustees Of Tufts College and Arisaph Pharmaceuticals, Inc. | Date: 2014-12-10

Disclosed are heterocyclylalkyl-substituted and heteroaralkyl-substituted pyridines, and pharmaceutically acceptable salts and prodrugs thereof, that are active against a range of mammalian therapeutic indications.

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