Thursday, April 3, 2025
4/3/2025
Medication Development for the Treatment of Alcohol Use Disorder - Nearly 15 million people in the US and ~100 million worldwide suffer from AUD. Over 5% of all medical morbidities share an ethanol-related risk. Although there are three FDA approved drugs to treat AUD, and several others are used off-label, medications have shown only modest success (~20%) in the treatment of patients. Consequently, there is an urgent need for new pharmacotherapeutics across the DSM-V AUD spectrum. Our approach in U01AA028957 was a straightforward medical chemistry research plan with IND-enabling studies followed by first in human safety clinical studies. A supplement is requested to meet unexpected expenses for Original Aim 1 and 2 with benefit to Aims 3 and 4. [Original Aims: 1: Development of manufacturing standards; 2: Completion of pre-clinical IND enabling studies; 3: Phase I clinical trial; single ascending dose; 4: Phase I clinical trial; multiple-ascending dose.] Specifically, based on the expertise of our consultants, we performed a CMC and nonclinical IND gap analysis. It was noted that additional IND-enabling nonclinical in vitro studies are important to the IND package for better understanding the distribution, metabolism, and excretion of 10-butyl ether minocycline (BEM) in rat, dog, and human. The proposed studies will provide a foundation in beginning to understand whether BEM could have potential risks for drug-drug interactions with concomitant medications. Estimations from Frontage Laboratories nonclinical studies is included within this supplement show a total of $252,550.00. The nonclinical studies proposed for execution using the supplemental funds include the following: 1) A plasma protein binding in mouse, rat, dog, and human study using rapid equilibrium dialysis to understand the bound and unbound BEM to plasma. 2) A red blood cell portioning study to assess the in vitro blood to plasma partition of fresh whole blood from rat, dog, and human. 3) Metabolic stability and 4) metabolite identification studies in mouse, rat, dog, and human hepatocytes. 5) A CYP reaction phenotyping study to identify the human cytochrome P450 (CYP) isozymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) responsible for metabolism and to understand the contribution of metabolism for each CYP isozyme. 6) A CYP inhibition study to evaluate the inhibitory and time-dependent inhibition potential of five major drug-metabolizing enzymes, CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4, using in vitro metabolic studies of representative index reactions catalyzed by human liver microsomes. 7) A CYP induction study to evaluate the CYP induction potential in cryopreserved human hepatocytes from 3 individual donors based on the gene expression of drug- metabolizing enzymes, CYP1A2, CYP2B6, CYP2E1, and CYP3A4. 8) A transporter study to determine whether BEM is transported by or inhibits transportation of human MDR1 (ABCB1/P-gp), BCRP (ABCG2), OATP1B1, and OATP1B3. The goal of this supplement request is to complete pre-IND activities that were not previously listed in the original application. We request $228,953 with the rest to be covered by other monies at a later time.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).