Advancing new options for treatment
By Dr Bob Anderson, Chief Scientific Officer, ImmusanT
New Zealand sites are participating in a major international research study to test an experimental treatment that aims to protect against the effects of inadvertent gluten exposure. People with medically-confirmed coeliac disease and following a gluten-free diet are being invited to participate in the study to test Nexvax2®. New Zealand volunteers, study sites and scientists have played a central role in the history of Nexvax2®, which is being developed by ImmusanT Inc., a biotech company based in Cambridge, Massachusetts USA.
Currently, there are no medications approved for the treatment of coeliac disease. Strict gluten free diet is the only management option. While there may be cases of misdiagnosis, particularly in patients who have excluded gluten before medical workup, common wisdom is that patients do not grow out of coeliac disease, and maintaining a strict gluten free diet is a medical necessity for life.
Ironically, while avoiding gluten improves chronic symptoms and reduces damage in the intestine, symptoms caused by gluten exposure can be more pronounced when gluten is not consumed regularly. Patients with coeliac disease are often “glutened”, and experience severe gastrointestinal symptoms within 2 hours. Over the last 2 years, our research has revealed that acute “gluten” symptoms are mirrored by pronounced elevations in blood levels of inflammatory cytokines that implicate T cells in the immune system as the frontline responders to gluten. When examined at a molecular level, the components of gluten that activate T cells in coeliac disease are highly consistent between individuals who share the same “gatekeeper” immune recognition genes – most often (in ~90% of patients) this is HLA-DQ2.5.
Seven years after leaving my home town of Dunedin in New Zealand, I found myself in a laboratory in Oxford, England thinking, “my life has just taken a different direction”. I was gazing with incredulity into a small plastic tray with strategically placed wells. For the previous 24 hours, the “plate” had contained blood from a volunteer with coeliac disease who was the first to complete a “3-day gluten challenge”. I had envisaged that this “glutening” might reactivate the immune response to gluten allowing me to find the fragments of gluten protein that stimulated T cells. Each pair of wells in the plate tested different pieces of a “classic” gluten‑protein called A-gliadin. To my delight, and subsequently the surprise of long-established researchers in coeliac disease, only one small region of the A-gliadin protein harboured the “toxic” sequence and, just as consequential, blood could now be used to measure the immune reaction causing coeliac disease. Coeliac disease now appeared to be due to a “whole body”, not just intestinal, immune reaction to gluten. These findings complemented parallel discoveries from other centres using T cells from intestinal samples, and have ultimately provided a comprehensive molecular understanding of the immune reaction to gluten. This was necessary for “rational” design and development of potential treatments, diagnostics, food tests and cereal breeding aimed at improving the medical and dietary management of coeliac disease.
Some of us began to see the potential for treating coeliac disease with a “vaccine” approach, utilizing key (toxic) gluten fragments recognized by T cells. The clear-cut findings from T cells in blood after a 3-day gluten challenge encouraged me to establish a research program in Melbourne at the Walter and Eliza Hall Institute (WEHI) in 2002. The work aimed at designing a “peptide-based therapeutic vaccine” to treat established coeliac disease, similar in principle to desensitization for allergies but without the risks of triggering allergic reactions. In 2003, the WEHI coeliac group doubled in size with the arrival of Dr. Jason Tye-Din, who continues to lead coeliac disease research at the institute. By 2006, sufficient data had been accumulated to allow “rational design” for Nexvax2. The first study of Nexvax2 in coeliac volunteers was completed in Melbourne in 2009. ImmusanT was founded in 2010 and has been developing Nexvax2 since that time.Dr. Bob Anderson moved to the US in 2012 and serves as Chief Scientific Officer.
Progress in Nexvax2 Development
Five early or so-called Phase-1 clinical trials have been completed that set the scene for the current Phase-2 ReSeT CeD study. Two clinical studies recruited patient volunteers from centres in New Zealand, with the Auckland site having the largest enrollment. These first studies, together with three additional Phase-1 clinical trials, taught us that coeliac symptoms are triggered by T cells rapidly responding to gluten peptides, and that the immune system can be retrained to ignore these gluten peptides by administering repeated doses of Nexvax2. We estimate this reprogramming using Nexvax2 can prevent responses to immune stimulation equivalent to the amount of gluten in about 2 loaves of bread.Based on their past involvement with the program, New Zealand centres are again being enlisted to enroll patients for Phase 2.
The recently initiated Phase-2 study is designed to show that regular Nexvax2 injections protect against the effects of “one-off” gluten exposure in patients doing their best to maintain a strict gluten-free diet.The trial is enrolling patients who have been on a gluten-free diet for a year and have had prior blood tests, and a stomach or duodenal biopsy, positive for celiac disease. The effectiveness of Nexvax2 is being compared with that of a placebo (or sham) treatment, and the study will take approximately 6 months for a patient to complete.Results from these types of trials are building blocks for rigorous (and repeated) demonstrations of efficacy and safety required by national health authorities to approve new medicines.(After successful completion of Phase 2, most drugs then go through a final confirmatory stage of Phase 3 clinical studies.)At this point, the goal with Nexvax2 is not to replace the gluten-free diet, but to protect against acute symptoms due to inadvertent gluten exposure, an all too common problem, faced by coeliac patients on a frequent basis.
Addressing the needs of patients with coeliac disease by providing treatment options on top of gluten free diet is the next milestone for a coeliac treatment. Drug development is a regimented and step-wise process, and this is how Nexvax2 is being studied. Having specific medications available for patients with coeliac disease should encourage added discipline, withwider use of appropriate diagnostic tests, and the establishment of new therapeutic benchmarks. Nexvax2, or another new drug, may someday meet these, including the possibility for allowing relaxation of dietary restrictions.However, at present, Nexvax2 is in clinical trials to establish its effectiveness as protection against inadvertent gluten exposure in patients on best available management, the gluten-free diet.
If you wish to participate in the ReSet CeD Study, you can contact one of the following participating sites:
Auckland Clinical Studies Ltd.
Ground Floor, 3 Ferncroft St
Grafton, Auckland 1010
Margaret Joppa Biscuit@clinicalstudies.co.nz
P: +64 9 373 3474 ext 105
F: +64 9 373 3479
P3 Research
1st Floor 121 Adelaide Road
Mount Cook
Wellington 6021
Mary McKay mary@p3research.co.nz
P: +64 4 801 0002
F: +64 4 389 7468
P3 Research - Havelock North
Ground Floor, 33 Napier Road
Havelock North 4130
HBTrials@p3research.co.nz
P: +64 6 824 3070 or 0800 141 559
Dr. Anderson graduated in medicine and has a doctorate from the University of Otago. His specialist training in internal medicine and gastroenterology was at The Royal Melbourne Hospital, and St Vincent’s Hospital in Melbourne. Dr. Anderson’s subsequent post-doctoral research at the University of Oxford focused on understanding the molecular basis for immune recognition of gluten in coeliac disease. He returned to Melbourne in 2002 and was a Laboratory Head at the Walter and Eliza Hall Institute. He also established dedicated clinics for coeliac disease at the Royal Melbourne Hospital and Alfred Hospital. He worked closely with Coeliac Australia and Coeliac New Zealand to raise public and health professional awareness for coeliac disease. Dr Anderson relocated to the United States in 2012 as Chief Scientific Officer of ImmusanT to continue his involvement in the development of Nexvax2 and advance similar peptide-based immunotherapies for other autoimmune diseases.