It might be the most common autoimmune condition but coeliac disease is an area that has struggled to attract the attentions of commercial drug makers over the years. Two major issues will have contributed to this aversion: difficulties in showing the benefit of any treatment over a gluten-free diet, and defining which patients should receive any successful treatment.
Therefore Glaxosmithkline’s acquisition of Sitari today catches the eye. The company is working on inhibitors of transglutaminase 2, an enzyme responsible for triggering the inflammatory cascade that occurs when sufferers ingest gluten. Work remains preclinical but the deal means that among the major drug developers, only the UK pharma giant and Takeda have an active interest in this space.
Sitari is also notable because the company was the first to be formed by a life science incubator set up by Glaxo and Avalon Ventures, back in 2013. No terms of the buyout were disclosed, and they are unlikely to be consequential to Glaxo. What is more interesting here is the strategic decision to move into a space that has seen very few projects progress.
|Active coeliac disease trials|
|Company/sponsor||Project||Mechanism||Trial ID||Primary completion|
|Innovate Biopharmaceuticals||INN-202||Intestinal tight junction regulator||NCT03569007||Aug 2021|
|Immunogenics||IMGX-003||Recombinant gluten-specific protease||NCT03585478||Feb 2020|
|Cour Pharmaceuticals||TIMP-Gliadin||Gliadin inhibitor||NCT03738475||Jul 2019|
|Dr Falk/Zedira||ZED1227||TG2 inhibitor||2017-002241-30||Unclear (started late 2018)|
|PVP Biologics (Takeda option)||Kuma-062||Gliadin inhibitor||NCT03701555||Dec 2019|
|NCI, Mayo Clinic||Humanized Mik-Beta-1 MAb||Anti-IL-15 antibody||NCT01893775||Jun 2020|
|Source: EvaluatePharma, clinicaltrials.gov, EudraCT.|
In fact, two of the most advanced agents in the industry’s pipeline have been around for years. Most advanced is Innovate Biopharmaceuticals’ INN-202, a compound that first went into the clinic in 2005. Since then it has passed through the hands of various owners, including Shire and Cephalon; Innovate licensed it from Alba Therapeutics in 2016.
Also known as larazotide acetate, the agent is thought to work by keeping closed so-called “tight junctions” in the bowel; in coeliacs, the presence of gluten causes tight junctions to open, starting an inflammatory cascade. Innovate dosed the first patient in a phase III trial of the project last month – the company claims this is the first pivotal study of a coeliac project to be conducted.
It is not entirely clear whether the company has the funds to complete the study, however: Innovate ended June with just over $13m in the bank. And this is not the only red flag. A phase IIb study, in 342 subjects, succeeded only at the lowest dose tested, so presumably the trial overall was a failure. This apparent lack of dose response has not deterred Innovate, which is testing the “successful” 0.5mg dose, and an even lower 0.25mg dose, in the pivotal trial.
Immunogenics, meanwhile, is working on a former Alvine-Abbvie project, latiglutinase, an oral mixture of two recombinant gluten-specific proteases, now coded IMGX-003. The company last month won a NIH grant to conduct a phase II trial in patients with type 1 diabetes and coeliac disease; the autoimmune diseases are genetically linked and there is a very high prevalence of coeliac patients found among the type 1 diabetic population.
Another 80-patient, NIH-sponsored, phase II trial is already ongoing with IMGX-003 and should yield results next year. However, this project also has a worrying history: Abbvie walked away after a large 500-patient phase II trial failed to show any benefit over placebo. The failure was blamed on the trial design, which caused the control arm to perform better than expected: all the patients displayed significant improvements in their symptom scores. Immunogenics is presumably convinced that there is a benefit to be teased out here somewhere.
The other notable mid-stage project is an irreversible TG2 inhibitor, ZED1227, which the private German company Dr Falk put into a 160-patient phase IIa study at the end of 2018. TG2, or tissue transglutaminase, is dysregulated in coeliac patients, and is considered to be the autoantigen that helps drive the destructive inflammatory cycle of the disease. The company hopes to show that blocking TG2 can break this cycle; the company declined to confirm to Vantage when results might emerge.
Earlier stage projects include a nanoparticle technology from Cour Pharmaceuticals. TIMP-GLIA is an encapsulated component of wheat protein, which the company hopes will help patients develop tolerance to gluten.
The primary completion date for this project's 51-patient trial has come and gone, though the private company has yet to announce any results. Cour forged a partnership with Takeda back in 2015 over its technology in coeliac disease, but with no news on that front since, the collaboration has presumably come to an end.
Takeda has shown an interest in the field elsewhere: it has an option over a phase I recombinant enzyme, Kuma062, being developed by the private US biotech PVP Biologics. The idea is that Kuma062 degrades the immune-reactive parts of gluten before they exit the stomach.
The Japanese company has the right to buy PVP should a phase I proof-of-principle study succeed; according to clinicaltrials.gov this is still recruiting patients.
Glaxosmithkline looks set to join Takeda with a clinical interest in this space in the coming months. However it is notable that when Vantage last looked at this space, back in 2013, the most advanced projects were also larazotide and latiglutinase. Sufferers must hope that some fresh approaches yield more progress in the coming years.
This article has been updated to include details on ZED1227.