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| Creating the next generation of cancer treatments |
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PIPELINEArno has exclusive worldwide rights to develop and market four innovative pre-clinical and clinical-stage anti-cancer product candidates with unique mechanisms of action. These compounds include three targeted agents and one cytotoxic compound that have the potential to be best- or first-in-class products for the treatment of hematologic malignancies and solid tumors.  OnapristoneDrug Description Onapristone is a progesterone receptor antagonist that has demonstrated anti-tumor activity in preclinical and clinical studies of hormone-dependent tumors. Its mechanism of action is thought to be a direct result of binding to the progesterone receptor and preventing the progesterone receptor from binding to DNA, thereby substantially reducing or eliminating progesterone-receptor-induced transcription resulting in death or differentiation of the malignant cells. Development History Onapristone was originally developed by Schering AG. Early stage clinical studies conducted in Europe in post-menopausal women with breast cancer showed encouraging anti-tumor activity but also transient elevated liver function test. Arno Therapeutics is conducting additional research to potentially identify patients who would benefit most from onapristone and has entered into a licensing agreement with Invivis Pharmaceuticals in 2012 for further development. Clinical Findings Onapristone has been evaluated in clinical studies as both first- and second-line treatment for primary and metastatic breast cancer. In clinical studies, onapristone has demonstrated a 56% objective response rate as a first-line endocrine treatment of breast cancer and a 49% clinical benefit rate in patients with breast cancer previously treated wiht tamoxifen. Future studies of onapristone may be conducted in combination with other endocrine agents to improve previous results observed in patients with breast cancer. Current Development Plan Arno plans to develop this compound for the treatment of a variety of tumor types, including breast and endometrial cancer. The company is preparing to conduct preclinical toxicology studies and has begun work on a predictive diagnostic biomarker to determine which patients would benefit most from onapristone treatment. Following completion of preclinical studies and initiation of the development of a companion diagnostic, we intend to file an IND with the FDA to begin a dose-escalation Phase I study of onapristone in patients with endometrial and breast cancer. Select Bibliography
AR-42Drug Description AR-42 is a novel, oral agent therapy currently in early clinical development. It is a broad-spectrum deacetylase inhibitor of both histone and non-histone proteins, which has demonstrated greater potency and activity in solid tumors and hematological malignancies when compared in preclinical studies to vorinostat (also known as "SAHA" or Zolinza®), the first of two marketed compounds in the class. AR-42 may possess additional histone-independent mechanisms, which may contribute to its superior profile in vitro and in vivo. It has been designated an orphan drug by the FDA for the treatment of meningioma and schwannoma of the central nervous system. Meningioma and schwannoma are rare, benign tumors that can present in different locations within the brain and the spinal cord and may cause substantial morbidity. Development History AR-42 was licensed to Arno in January 2008 by The Ohio State University Research Foundation for commercial development by Arno. Preclinical Findings In preclinical models, AR-42 has shown to be more potent or effective than SAHA in various cancer types, including chronic lymphocyte leukemia, or CLL, B-cell lymphoma, prostate and ovarian cancers. Preclinical studies suggest that AR-42 has anti-cancer activities that are independent of histone acetylation and which disrupt the growth and proliferation of cancer cells. We believe that this combination of activity and potency could make AR-42 a more effective treatment for hematological malignancies than currently available HDAC inhibitors and a potential treatment of a number of solid tumors. In addition, pre-clinical models have demonstrated anti-tumor activity in tumor types (schwannoma and meningioma) that are associated with the genetic illness neurofibromatosis type 2. Additional pre-clinical data presented at the 2009 American Society of Hematology Annual Meeting showed that AR-42 potently and selectively inhibits leukemic stem cells in acute myeloid leukemia. Development Plan AR-42 is currently in an investigator-initiated dose-ranging Phase I/IIa clinical trial for treatment of relapsed or recurrent hematological malignancies and solid tumors for which standard treatment has failed or not proven to be effective. The ongoing study is designed so that additional patients with hematological malignancies can be added to investigate the potential efficacy of AR-42 in a particular disease and help guide future Phase II programs once the recommended dose for further study has been defined. During 2012, we intend to collaborate with The Ohio State University to conduct an investigator-initiated study of AR-42 in patients with schwannoma and meningioma to assess intra-tumoral concentrations of AR-42, identify apoptosis markers and assess gene regulation. CLINICAL PROGRAM For information about the current clinical program, please Click Here AR-12Drug Description AR-12 is a potentially first-in-class, orally available, targeted anti-cancer agent that has been shown in preclinical studies to inhibit phosphoinositide-dependent protein kinase-1, or PDK-1, a protein in the PI3K/Akt pathway that is involved in the growth and proliferation of cells, including cancer cells. Although FDA-approved drugs that target the Akt pathway have shown efficacy in treating cancer, some tumors either do not respond to these drugs or eventually become resistant to therapy. Scientists hypothesize that a combination of drugs that inhibit different targets in this pathway could provide synergistic or additive benefits to increase efficacy and potentially overcome drug resistance. For this reason, there has been particular interest within the biopharmaceutical industry in developing inhibitors of PI3K, PDK-1, and Akt. Development History AR-12 was licensed to Arno in January 2008 by The Ohio State University Research Foundation for commercial development by Arno as a potential treatment for solid tumors and hematological malignancies. Preclinical Findings In preclinical studies, AR-12 has shown efficacy in a wide range of tumor types, including breast, lung, prostate, pancreatic, brain and hematological cancers, as both a single-agent as well as in combination with leading oncology therapeutics. AR-12 demonstrated synergy or additive benefit or overcame drug-resistance when used in combination with Avastin®, Herceptin®, Gleevec®, Tarceva®, Iressa®, Nexavar® and tamoxifen, all of which are widely prescribed, FDA-approved oncology therapeutics that, according to Thomson Reuters Pharma, represented approximately $17 billion in sales in 2009. Development Plan We are currently conducting a multi-centered, two-part, Phase I clinical study of AR-12 in adult patients with advanced or recurrent solid tumors or lymphoma. The first part is a dose-escalating study to evaluate the safety of AR-12 and identify the maximum tolerated dose and recommended Phase II dose for future studies. The second part of the study was to be a cohort expansion at the recommended phase 2 dose in selected "tumor types". We will not be proceeding with the second part of the study, as we plan to develop a revised formulation of AR-12 with greater bioavailability which will require a new Phase I study to be performed. Select Bibliography
For information about the current clinical program, please go to Click Here AR-67Drug Description AR-67 is a novel, third-generation camptothecin analogue that has demonstrated high potency in pre-clinical studies and improved pharmacokinetic properties in humans as compared with first and second-generation products. Camptothecins treat cancer by disrupting cell division through the inhibition of topoisomerase I, a critical enzyme in DNA replication. Through this inhibition and additional mechanisms of action, camptothecins represent an established class of oncology drugs, with worldwide annual sales exceeding $660 million, according to Thomson Reuters Pharma. AR-67 is being studied as a potential treatment for glioblastoma multiforme (GBM). Development History AR-67 was licensed to Arno in October 2006 by the University of Pittsburgh for commercial development by Arno. In 2008, we completed a multi-centered, ascending-dose Phase I clinical trial of AR-67 in patients with advanced solid tumors. In December 2009, we initiated an open-label Phase II study of AR-67 in patients with GBM, the most prevalent and deadly form of brain cancer. In June 2011, we announced that the Phase II study met pre-defined interim goals for patients with GBM who were not previously treated with Avastin® and that the study would continue toward completion. Previous Findings AR-67 has demonstrated the potential for increased central nervous system penetration and more predictable metabolism and toxicity than current camptothecin analogues. A Phase I study demonstrated anti-tumor activity, acceptable safety (no drug related diarrhea) and linear pharmacokinetics. Development Plan We are conducting a Phase II clinical study of patients with GBM to evaluate the safety and efficacy of AR-67 as a treatment for patients with GBM who have progressed on other therapies. This study has two separate groups of patients; the first cohort enrolled patients who had progressed rapidly (within 90 days) after treatment with Avastin®. These patients' cancer normally behaves quite aggressively, and the endpoint for this cohort was two months of progression-free survival. We closed enrollment in this cohort due to a lack of clinical response among the first 13 patients who were enrolled. The second cohort enrolled 32 subjects who had not received Avastin® or had not received Avastin® treatment in the past 90 days. The second cohort group treatment is ongoing and it anticipated to have the final data analysis by Q4-2012 - Q1-2013. CLINICAL PROGRAM For information about the current clinical program, please Click Here | | 
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