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Jefferson Adams posted an article in Celiac Disease Diagnosis, Testing & TreatmentCeliac.com 11/05/2018 - ImmusanT, Inc. is a clinical stage company looking to deliver innovative peptide-based immunomodulatory vaccine therapies to patients with autoimmune diseases, initiated enrollment in Australia and New Zealand for its celiac disease vaccine. Along with Nexvax2, ImmusanT is working to develop vaccines for other HLA-associated autoimmune diseases, including type 1 diabetes. The Phase 2 trials will assess the safety, tolerability and efficacy of its celiac vaccine, Nexvax2, on celiac patients who carry the immune recognition genes for HLA-DQ2.5. Carriers of HLA-DQ2.5 account for approximately 90% of people with disease, and Nexvax2 is designed to protect these patients from the effects of gluten exposure. Nexvax2 is currently the only disease-modifying therapeutic candidate in clinical development for patients with celiac disease. Injections of Nexvax2 are designed to reprogram T cells that trigger an inflammatory response to gluten, thereby suppressing inflammation in patients with celiac disease. Phase 1 studies showed Nexvax2 to be safe and well-tolerated at even its highest dose levels. In Phase 2 clinical trials, ImmusanT hopes to confirm clinical efficacy of Nexvax2 administered by injection into the skin for treatment of celiac disease. The study plan consists of an initial screening period of 6 weeks, an approximately 16 week treatment period, and a 4 week post-treatment observational follow-up. The trials will be conducted at sites in Melbourne, Perth, Adelaide and Brisbane, in addition to sites in New Zealand. For the U.S. study researchers will enroll approximately 150 patients across the U.S., Australia and New Zealand. Phase 2 is a randomized, double-blind, placebo-controlled clinical study of Nexvax2 in adults with confirmed celiac disease who have followed a gluten-free diet for at least a year prior to screening. “This trial is important in establishing clinical proof-of-concept for a treatment that would provide benefit beyond that of the gluten-free diet,” and will “test if Nexvax2 can specifically target the immune response to gluten in people with celiac disease and modify associated symptoms,” said Jason Tye-Din, MBBS, Ph.D., principal investigator at the Royal Melbourne Hospital and head of celiac research at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. For more information about RESET CeD, including inclusion and exclusion criteria, please visit www.clinicaltrials.gov (Identifier: NCT03644069).
Jefferson Adams posted an article in Diabetes and Celiac DiseaseCeliac.com 10/19/2018 - Work to develop a vaccine for celiac disease could soon lead to a vaccine for diabetes. After successful phase 1 studies of Nexvax2, their peptide-based therapeutic vaccine for celiac disease, ImmusanT has seen a significant investment from venture philanthropy organization JDRF T1D. ImmusanT's peptide therapy program for celiac disease may provide lessons for a similar therapeutic treatment for Type 1 diabetes. The investment will support ImmusanT as it attempts to develop a vaccine to prevent Type 1 diabetes, based on the early success of its peptide immunotherapy program for celiac disease, the two entities announced in a press release. ImmusanT’s celiac peptide therapy program works by identifying antigens that trigger an inflammatory responses in people with autoimmune diseases. Once identified, the peptide therapy is used to neutralize the autoimmune response. This celiac disease program goes back to 1998, when Anderson first began his efforts to find and identify the peptides. The findings were published in 2010, and the company was founded shortly afterward by Leslie Williams, BS, RN, MBA, director, president and CEO of ImmusanT. From there, ImmusanT conducted five phase 1 trials for its celiac therapy. Those trials have proven very promising, and the latest investment into a similar drug for diabetes is proof of that promise. In the case of celiac disease, the drug works by “targeting T cells in patients. Those T cells that are engaged as peptides are distributed throughout the body after the injection, and we see evidence that the T cells are being activated about 2 hours later,” Robert Anderson, BMedSc, MB, ChB, PhD, FRACP, chief scientific officer for ImmusanT, told Endocrine Today. “We found that if we gradually increase the dose in patients building up to a maintenance dose level, they become non-reactive to those peptides.” With much of the early research targeted towards demonstrating the drug’s safety, and getting the right dose and dose regimen, the development of a version targeted at diabetes, says Anderson, “should be more streamlined due to the lessons learned during the celiac disease program. That’s partly because the team knows “a lot more going into Type 1 diabetes about how peptide therapy works and how to optimize it than we did when we started celiac disease, where it was a blank slate.” This is really exciting news. A vaccine for celiac disease is exciting, to be sure, but a viable vaccine for diabetes would be a major development in disease prevention. Stay tuned for more news as the story develops. Read more at Healio.com
Jefferson Adams posted an article in Celiac Disease Diagnosis, Testing & TreatmentCeliac.com 05/29/2017 - Currently, a gluten-free diet is the only way to manage celiac disease. Can a celiac vaccine change that? One company thinks so. ImmusanT corporation has developed a therapeutic vaccine, Nexvax2, that is specifically designed to treat celiac disease. The vaccine is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is designed to neutralize gluten-specific CD4-positive T cells to further antigenic stimulation. As part of their efforts to evaluate the vaccine, a team of researchers recently set out to investigate the efficacy of epitope-specific immunotherapy targeting CD4-positive T cells in celiac disease. Specifically, they assessed the safety and pharmacodynamics of the Nexvax2 vaccine in patients with celiac disease on a gluten-free diet. An article detailing the findings of their most recent effort, titled Epitope-specific immunotherapy targeting CD4-positive T cells in celiac disease: two randomized, double-blind, placebo-controlled phase 1 studies, appeared in the Lancet. The research team included Gautam Goel, PhD, Tim King, MBBChir, A James Daveson, MBBS, Jane M Andrews, MBBS, Janakan Krishnarajah, MBBS, Richard Krause, MD, Gregor J E Brown, MBBS, Ronald Fogel, MDCM, Charles F Barish, MD, Roger Epstein, MD, Timothy P Kinney, MD, Philip B Miner Jr, MD, Jason A Tye-Din, MBBS, Adam Girardin, BS, Juha Taavela, MD, Alina Popp, MD, John Sidney, BS, Prof Markku Mäki, MD, Kaela E Goldstein, BS, Patrick H Griffin, MD, Suyue Wang, PhD, John L Dzuris, PhD, Leslie J Williams, MBA, Prof Alessandro Sette, DrBiolSc, Prof Ramnik J Xavier, MD, Prof Ludvig M Sollid, MD, Prof Bana Jabri, MD, and Dr Robert P Anderson, MBChB. To assess the safety and pharmacodynamics of the vaccine in patients with celiac disease on a gluten-free diet, ImmusanT recently conducted two randomized, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18–70 years who had celiac disease and were following a gluten-free diet. The goal of the study was to document the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. The study enrolled a total of 108 participants from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. None of the study participants, investigators, or staff knew which patients received a given treatment; these details were known only by the study’s lead pharmacist. In the three-dose study, participants received either Nexvax2 60 μg, 90 μg, or 150 μg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or a placebo. In the 16-dose study, participants received Nexvax2 150 μg or 300 μg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or a placebo. In both studies, about 5% of the participants reported were vomiting, nausea, and headache. Among participants given the MTD, four of eight subjects in the third cohort experienced adverse gastrointestinal treatment-emergent events; zero of three participants had adverse events in the biopsy cohort in the three-dose study, while five events occurred in five (63%) of eight participants in the first cohort, and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Those who received the vaccine at the MTD on either schedule showed no significant difference between average villous height to crypt depth ratio in distal duodenal biopsies, as compared with those who received placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence. Meanwhile, biopsy cohorts received a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative in two (22%) of nine placebo-treated participants in the three-dose study. Compared with two (33%) of six who received Nexvax2 60 μg, five (63%) of eight who received Nexvax2 90 μg, and six (100%) of six who received Nexvax2 150 μg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 μg (p=0·021). The MTD of Nexvax2 was 150 μg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides with no adverse impact on duodenal histology. Patients who received the intradermal administration of the vaccine reported gastrointestinal symptoms were not subtantially different to those seen with oral gluten challenge. While the commercial release of a viable vaccine is likely still some time away, early-phase trials have shown promise. Based on these results, ImmusanT will continue clinical development of this potentially therapeutic vaccine for celiac disease. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. Source: The Lancet Affiliations: The researchers are variously affiliated with the Division of Gastroenterology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA, the Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA; the Department of Gastroenterology, Auckland City Hospital, Auckland, New Zealand; the School of Medicine, University of Queensland, Brisbane, QLD, Australia; the Department of Gastroenterology & Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia; the Linear Clinical Research, Nedlands, WA, Australia; the Department of Gastroenterology, Alfred Hospital, Prahran, VIC, Australia; the Clinical Research Institute of Michigan, Chesterfield, MI, USA; the University of North Carolina School of Medicine, Chapel Hill, NC, USA; Wake Gastroenterology and Wake Research Associates, Raleigh, NC, USA; Atlantic Digestive Specialists, Portsmouth, NH, USA; Ridgeview Medical Center, Waconia, MN, USA; Oklahoma Foundation for Digestive Research, Oklahoma City, OK, USA; ClinSearch, Chattanooga, TN, USA; the Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; the Murdoch Children's Research Institute and Department of Gastroenterology, Royal Melbourne Hospital, Parkville, VIC, Australia; the Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; the Tampere Center for Child Health Research and Department of Pediatrics, University of Tampere Faculty of Medicine and Life Sciences and Tampere University Hospital, Tampere, Finland; the Tampere Center for Child Health Research and Department of Pediatrics, University of Tampere Faculty of Medicine and Life Sciences and Tampere University Hospital, Tampere, Finland; the Alfred Rusescu Institute for Mother and Child Care and Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA; the Tampere Center for Child Health Research and Department of Pediatrics, University of Tampere Faculty of Medicine and Life Sciences and Tampere University Hospital, Tampere, Finland; the Centre for Immune Regulation, KG Jebsen celiac Disease Research Centre, and Department of Immunology, University of Oslo, Oslo, Norway; the Oslo University Hospital-Rikshospitalet, Oslo, Norway; Department of Pediatrics, Department of Medicine, University of Chicago, Chicago, IL, USA; and ImmusanT in Cambridge, MA, USA.
Jefferson Adams posted an article in Celiac Disease Diagnosis, Testing & TreatmentCeliac.com 01/04/2018 - Nexvax2 is a peptide-based, epitope-specific immunotherapy intended to reduce reactions to natural gluten exposure, and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients who received fixed intradermal doses of Nexvax2 lost their sensitivity to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but their tolerance was limited to 150 μg, due to gastrointestinal symptoms and cytokine release, mimicking gluten exposure, that accompany the first dose. A team of researchers recently set out to test whether small doses in steps might reduce the first dose effect of Nexvax2 in celiac disease patients. The research team included James M. Daveson, Hooi C. E, Jane M. Andrews, Timothy King, Kaela E. Goldstein, John L. Dzuris, James A. MacDougall; Leslie J. Williams, Anita Treohan, Michael P. Cooreman, and Robert P. Anderson. They are variously associated with the Faculty of Medicine, University of Queensland, QLD, Australia b Department of Gastroenterology, Sir Charles Gairdner Hospital, WA, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, SA, Australia; Department of Gastroenterology, Auckland City Hospital, Auckland, New Zealand; PROMETRIKA, LLC, Cambridge, MA, USA; and ImmusanT Inc., Cambridge, MA, USA. The team conducted a randomized, double-blind, placebo-controlled trial at four community sites in Australia (3) and New Zealand (1) in HLA-DQ2·5 genotype positive adults with celiac disease who were on a gluten-free diet. By using doses escalated from 3 μg up to 300 μg in HLA-DQ2·5 homozygotes or to 900 μg in HLADQ2.5 non-homozygotes the team was able to eliminate the adverse events and cytokine release that had limited the previous maximum dose to 150 μg. Administration of Nexvax2 at dose levels from 150 μg to 900 μg preceded by dose escalation was not associated with elevations in plasma cytokines at 4 h. Otherwise, the most common treatment-related side effects in the Nexvax2 participants were headache (52%), diarrhea (48%), nausea (37%), abdominal pain (26%), and abdominal discomfort (19%). This study shows that antigenic peptides recognized by CD4-positive T cells in an autoimmune disease can be safely administered to patients at high maintenance dose levels without immune activation when preceded by gradual dose escalation. These findings help further these efforts to develop a successful immunotherapy drug to treat celiac disease. Read more at Ebiomedicine.com This completed trial is registered with ClinicalTrials. gov, number NCT02528799.