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Pharmacological characterization and validation.
• In vitro cell proliferation, differentiation and apoptosis studies.
• RNA-sequencing experiments; gene enrichment sequencing analyses in order to identify key components of cellular pathways that are modulated by the OST-1 (or other derivatives) and that lead to cancer cell death.
• Proteomics and metabolomics studies will be carried out using state of the art mass-spectrometry techniques to evaluate the ability of OST-01 and derivatives to modulate protein synthesis post-translational modification, activation, and metabolism in AML and other cancer cells.
• CRISPR screening which uses a powerful gene editing tool that cuts DNA in a precise, directed manner will also be carried out to identify key gene products that are the potential targets for anti-leukemic activity of OST-01 and derivatives.
• Efficacy Studies. Dose-searching and efficacy studies and patient- derived xenograft (PDXs) models.
• Preliminary Toxicology. In addition to cage side observations and weights, major organs and tissues from mice treated with OST-01 or derivatives will be surveyed for toxicity using a range of doses in mice. A licensed veterinary pathologist assists in the evaluation of the results.
• Mass-spectrometry studies will be pursued to identify the active principle(s) contained OST-01 and those of other OST derivatives.
• Validation studies utilizing individual basic components of OST-01 OST-derivatives will be pursued.
• Having identified the active principle(s) of OST-01 and OST-derivatives (see Phase II-1) and the corresponding targets (or biological endpoint; see Phase I-1), we will proceed with in vivo pharmacokinetics (PK) and pharmacodynamics (PD) studies. Mathematical modeling of these results will be conducted to identify an optimal dose/schedule of OST-01 and OST-derivatives with the maximal activity, less frequent administration and highest safety.
• Efficacy studies in the in vivo models of AML and other cancer (e.g., breast, colon, lung) will be pursued to validate the optimal doses/schedules predicted by the PK/PD modeling and to compare the activity of OST-01 with that of other OST-derivatives. The most effective and tolerated compound with the most feasible schedule of administration less will be pursued for IND enabling studies.
IND ENABLING TOXICOLOGY STUDIES:
This phase includes a list of requirements by the FDA to apply for the status of an IND. Once the status of IND is secured, Ostentus Therapeutics can proceed to clinical trials. An approved IND is a “key” step in the development of a new drug.
• To pursue an IND application with the FDA, Ostentus Therapeutics will establish a Good Laboratory Practices (GLP) manufacturing process of the leading candidate. The GLP compound will be used in GLP toxicology studies conducted through a licensed Contract Research Organization (CRO). The GLP toxicology will be synthesized in the Ostentus Therapeutics’ good manufacturing practice facility and will serve as the test article for the IND-enabling toxicology studies in at least two species other than mice as required by the FDA.
• According to FDA guidance documents, the maximum recommended starting dose of a new drug for a first-in-human trial must be no more than 0.1 x of the maximum no observable adverse effect level established in the most sensitive species tested. Thus, the toxicology studies entail studying the OST candidates within a log-range of doses and different routes (oral, intravenous, intralesional) and schedule of administration. These studies will be performed at a specialized CRO site.
• Blood samples will be obtained for PK/PD studies from individual animals utilized in the toxicology studies. In addition, blood and urine, necropsies, other organ tissues with be obtained and prepared by the CRO, for evaluation by a US licensed veterinary pathologist retained by the CRO.
• All available protocol specified tissues from all study animals at planned sacrifice times and from animals found dead or moribund (and therefore sacrificed), as well as all gross lesions in all animals, will be evaluated and the data submitted directly to the FDA.
FDA Filing
The IND application must contain information in three broad areas:
• Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experiences with the drug in humans (often foreign use).
• Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
• Clinical Protocols and Investigator Information - Detailed protocols for the proposed first in-human clinical study will be submitted along with the toxicology, PK-PD data and efficacy results. Also, information on the qualifications of clinical investigators will who oversee the OST compound and monitor the subjects for toxicity will also be submitted.
Finally, it is expected that Ostentus Therapeutics show proof of commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations. The FDA will review the IND application to assure that research subjects will not be subjected to unreasonable risk. If all the data provided are satisfactory, the FDA will grant an IND status, and IRB-approved clinical trial can be started.
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