A Phase 1b, Randomized, Single-blind, Placebo-controlled, Multiple Ascending Dose (MAD) Study to Assess the Steady-State Pharmacokinetics and DQ8 Blocking Efficacy of Orally Administered IMT-002 in Patients With Type 1 Diabetes and HLA-DQ8

This study is designed to characterize the safety, steady-state pharmacokinetics (PK) of IMT-002, and will serve as a dose range identification for the pharmacodynamic effect of blocking self-antigen presentation in adults with type 1 diabetes (T1D) having the human leukocyte antigen (HLA)-DQ8 gene.

开始日期2020-11-09

申办/合作机构

ImmunoMolecular Therapeutics, Inc.初创企业

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项与 D-methyldopa 相关的文献（医药）

2024-05-16·Blood

Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma

Article

作者: Chretien, Marie-Lorraine ; Manier, Salomon ; Jobert, Alexandra ; Corre, Jill ; Touzeau, Cyrille ; Leleu, Xavier ; Macro, Margaret ; Planche, Lucie ; Jacquet, Caroline ; Perrot, Aurore ; Moreau, Philippe ; Escoffre, Martine ; Tiab, Mourad ; Karlin, Lionel ; Hulin, Cyrille ; Avet-Loiseau, Herve

Abstract:

High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation–related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10–6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577.

2024-04-01·PEDIATRIC ANESTHESIA

New postoperative pain instrument for toddlers-Secondary analysis of prospectively collected assessments after tonsil surgery.

Article

作者: Gude, P ; Gustedt, F ; Weber, T P ; Georgevici, A I ; Geldermann, N ; Grobe, C

BACKGROUND:

The Children's and Infant's Postoperative Pain Scale (CHIPPS) and the German version of the Parent's Postoperative Pain Measure (PPPM-D) are used to assess postoperative pain intensity in preschool children. However, they have shown low concordance in previous prospective studies on quality improvement.

AIMS:

Our secondary analysis aimed to estimate the association strength between the pain score items and indication for rescue medication defined as CHIPPS ≥4 and/or PPPD-D ≥ 6. Thus, we intended to create a further developed pain instrument with fewer variables for easier routine use.

METHODS:

We analyzed 1067 pain intensity assessments of hospitalized children for the development of our novel tool in two steps using modern statistical and machine-learning methods: (1) Boruta variable selection to analyze the association strength between CHIPPS score, PPPM-D items, age, weight, and elapsed time after surgery, including their interactions and pattern stability, and the binary outcome (analgesics required yes/no). (2) Symbolic regression to generate a short formula with the least number of variables and highest accuracy for rescue medication indication.

RESULTS:

Additional analgesics were required in 19.96% of pain intensity assessments, whereby the PPPM-D showed higher variance than CHIPPS. Boruta identified PPPM-D score, CHIPPS score, 9 of the 15 PPPM-D variables, and time of assessment as associated with the indication for RM. Symbolic regression revealed that additional analgesics are required if CHIPPS is ≥4 OR PPPM-D item "less energy than usual" AND one of the items "more easily cry" or "more groan/moan" are answered with "yes." These PPPM-D items were not redundant and showed nonlinear course over time. The cross-validated accuracy for this assessment tool was 94.94%.

CONCLUSIONS:

The new instrument is easy to use and may improve postoperative pain intensity assessment in children. However, it requires prospective validation in a new cohort.

2024-01-01·Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)

Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action

Article

作者: Williams, Patricia A M ; De Giusti, Verónica ; Velez Rueda, Jorge O ; Portiansky, Enrique L ; Ferrer, Evelina G ; Martinez, Valeria R ; Actis Dato, Agustin B

BACKGROUND:

the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H₂O)₂]·H₂O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD.

METHODS:

ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl₂ were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91^phox and p47^phox) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis.

RESULTS:

The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment.

CONCLUSION:

Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

项与 D-methyldopa 相关的新闻（医药）

2021-04-06

·BioSpace

IM Therapeutics Expands Management Team with David Alleva, Ph.D. as VP, Immunology

April 6, 2021 12:00 UTC Broadens immunology expertise to expand company pipeline in genetically targeted oral therapies for autoimmune diseases WOBURN, Mass.--(BUSINESS WIRE)--IM Therapeutics, Inc., a clinical-stage company developing novel, first-in-class therapies targeting human leukocyte antigens (HLAs) to treat autoimmune diseases, announced today that David Alleva, Ph.D., has joined its management team as Vice President, Immunology. Dr. Alleva is an immunologist with deep experience in R&D in autoimmunity and infectious disease spanning 22 years and across early-stage biotech, foundations, and clinical-stage biopharmaceutical organizations. IM Therapeutics’ IMT-HALT™ platform enables the development of oral small molecule drugs to block HLA gene variants as the earliest triggers of autoimmunity. The Company’s lead drug candidate, IMT-002, is in a Phase 1b study in type 1 diabetes (T1D) in patients genetically preselected for HLA-DQ8. HLA-DQ8 significantly increases the risk for T1D and is present in 60% of T1D patients. “I am excited to welcome David to our leadership team and impressed by his work in novel approaches in T1D and the autoimmune spectrum,” said Nandan Padukone, Ph.D., CEO of IM Therapeutics. “David broadens our expertise at a pivotal time as we advance our lead program in T1D through Phase 1 clinical trials and progress our additional programs. David’s advocacy for new ways to treat T1D and his immunotherapy drug development experience will be tremendous assets to the company as we expand our autoimmune-targeted pipeline.” Dr. Alleva has been in senior R&D management positions, most recently at Akston Biosciences where he led immunotherapy development for T1D and a COVID-19 vaccine program. Previously, he led several R&D programs with ADiTx in T1D, managed portfolio programs at JDRF, and helped advance drug development of small-molecules, biologics, and vaccine therapeutics at Emergent BioSolutions, Hollis-Eden Pharmaceuticals, XOMA, and Neurocrine Biosciences. Dr. Alleva earned a Ph.D. in immunology from the Virginia Polytechnic Institute and State University and performed postdoctoral autoimmune disease research at Boston University Medical Center. He has authored more than 30 peer-reviewed publications, has chaired immunology conferences, and is on the Editorial Board for the Biomedicines MDPI journal. “HLA drug targeting holds great promise and I am very excited by the progress made by IM Therapeutics to tap into this genetically-directed approach for T1D and other autoimmune diseases,” said Dr. Alleva. “I look forward to joining this dynamic team and bringing forward new personalized medicines to treat the underlying biology of autoimmunity.” About IMT-002 IMT-002, the lead drug candidate of IM Therapeutics, is the first oral genetically targeted drug candidate to be tested in T1D patients, an incurable autoimmune disorder that affects nearly 1.6 million people in the United States. IMT-002 completed a Phase 1a study in 2020 and is currently completing a Phase 1b study in T1D patients preselected for the HLA-DQ8 gene variant. IMT-002 is designed to block HLA-DQ8 to prevent the immune system from attacking insulin-producing beta cells, thereby preserving function in newly diagnosed patients, and is being investigated as a once- or twice-daily drug candidate. Previous studies of a tool drug, L-methyldopa, which is FDA-approved for treating hypertension, in a Phase 1b study, showed effective inhibition of HLA-DQ8 activity in new onset type 1 diabetes patients who had the HLA-DQ8 gene variant. Several in vivo IND-enabling studies indicate that IMT-002, which unlike the tool drug, is not metabolized physiologically, has more potency to block HLA-DQ8 activity and a favorable safety profile. About IM Therapeutics IM Therapeutics is a clinical-stage company pioneering personalized, oral medicines that target human leukocyte antigen (HLA) gene variants to treat the root cause of autoimmune diseases. The Company’s IMT-HALT platform enables the development of small molecule drugs using in silico docking of millions of compounds into pockets of an HLA variant where self-antigens may bind to trigger autoimmunity. Selected drug hits are then optimized using proprietary structure-based design and activity screening with cell-based assays for specificity of HLA inhibition. Lead drugs developed against an HLA variant have the ability to block a series of self-antigens and therefore the potential to treat a range of autoimmune diseases related to a selected HLA. The Company is building a broad HLA-targeted pipeline in autoimmune disorders including type 1 diabetes, celiac disease, and lupus. Learn more at .

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2021-01-27

·BioSpace

IM Therapeutics Announces Appointment of Jonathan Rigby to Board of Directors

WOBURN, Mass.--(BUSINESS WIRE)-- ImmunoMolecular Therapeutics, Inc. (“IM Therapeutics”), a clinical stage company developing personalized therapies for autoimmune disease, announced today that Jonathan Rigby has joined its Board of Directors. Mr. Rigby brings extensive company building and pipeline development experience in autoimmune and other diseases. IM Therapeutics is developing small molecule oral genetic medicines targeting specific human leukocyte antigen (HLA) variants known to play a strong role in autoimmune diseases. The Company’s lead drug candidate, IMT-002, is in Phase 1b clinical trials in type 1 diabetes (T1D). Patients in the study were preselected for HLA-DQ8, the gene variant present in about 60% of T1D patients. “Jonathan brings a strong corporate development and drug development perspective to our team as we position our technology platform towards multiple autoimmune conditions,” said Nandan Padukone, Ph.D., CEO of IM Therapeutics. “He is a great asset to the company as we complete Phase 1 studies in T1D, prepare for Phase 2 through early next year, and build our pipeline in celiac disease and other autoimmune diseases.” Mr. Rigby has three decades of experience building biopharmaceutical companies from early stages to IPO and acquisitions. He is currently President and Group CEO and a member of the Board of Immune Regulation Ltd, a company involved in developing novel treatments for autoimmune and allergic diseases. Previously, he established SteadyMed Therapeutics Inc, (NASDAQ IPO 2015, STDY), acquired by United Therapeutics (Nasdaq: UTHR) in 2018, and Zogenix, Inc. (NASDAQ IPO 2010, ZGNX). Prior to Zogenix, he worked at Aradigm Corp, a leader in the development of inhaled insulin, and held commercial and business development positions at Merck, Bristol Myers Squibb and Phillips Medical. Mr. Rigby currently serves on the Board of Directors of Thermalin Inc., and previously Xeris Pharmaceuticals (Nasdaq: XERS); and Chairman of CollPlant Biotechnologies, (Nasdaq: CLGN). He holds a Bachelor of Science Degree, with Honors, in Biological Sciences from Sheffield University, UK, and an MBA from Portsmouth University, UK. “I have a deep connection with autoimmune disease management, particularly type 1 diabetes, and am fascinated with the oral targeted drug approach of IM Therapeutics directed at genetic targets,” said Mr. Rigby. “I am also impressed by the clinical progress the team has achieved with IMT-002 as a lead drug in a short period of time and in the midst of a pandemic.” About IMT-002 IMT-002, the lead drug candidate of IM Therapeutics, is the first oral genetically targeted drug candidate to be tested in T1D patients, an incurable autoimmune disorder that affects nearly 1.6 million people in the United States. IMT-002 completed a Phase 1a study in August 2020 and is currently recruiting patients in a Phase 1b study in T1D preselected for the HLA-DQ8 gene variant. IMT-002 has been developed as a selective HLA-DQ8 blocker based on extensive computational work, in vitro and in vivo characterization. Previous studies of a tool drug, L-methyldopa, which is FDA-approved for treating hypertension, in a Phase 1b study, showed effective inhibition of DQ8 activity in new onset type 1 diabetes patients who had the DQ8 gene variant. Several in vivo IND studies indicate that IMT-002, which unlike the tool drug, is not metabolized physiologically, has more potency to block DQ8 activity and a favorable safety profile. About IM Therapeutics IM Therapeutics ( ) is a clinical stage company developing personalized medicines for autoimmune diseases by creating oral medicines against human leukocyte antigen (HLA) variants known to confer high risk of disease. The Company’s technology platform develops small molecule drugs using in silico docking of millions of compounds into pockets of an HLA variant where self-antigens may bind to trigger autoimmunity. Selected drug hits are then optimized using proprietary structure-based design and activity screening with cell-based assays for specificity of HLA inhibition. Lead drugs developed against an HLA variant have the ability to block a series of self-antigens and therefore the potential to treat several autoimmune indications related to a selected HLA. The Company is building a broad HLA-targeted pipeline in autoimmune disorders including type 1 diabetes, celiac disease, and lupus.

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100 项与 D-methyldopa 相关的药物交易

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