This is my first update on the Diamyd company in many, many years. It is focused on their DIAGNODE-3 clinical trial, but before I discuss that one study, I cover Diamyd's history, and after I discuss the study, I've included a list of all the studies the company has done (which is a lot: about 19 studies in about 20 years).
But that is not all that Diamyd is active with. In a future blog, probably in February, I'm going to discuss two more clinical trials which are important to applying Diamyd to at-risk people and people with LADA. DIAGNODE-3 is focused on honeymooners. That future blog will also include some interesting discussion of JDRF's funding of Diamyd.
The drug Diamyd is a form of GAD65. GAD65 is an enzyme, which is common in the pancreas and is used to make GABA and it is also a target of the immune system which can cause type 1 diabetes. The company Diamyd believes that the drug Diamyd works by teaching immune cells not to attack beta cells and therefore beta cells will not be destroyed at the onset of T1D. The technical phrase for this is "antigen-specific tolerizing beta-cell preserving therapeutic". It is also sometimes called a reverse vaccine, because it teaches your immune system not to attack a specific kind of cell (your beta cells), while a standard vaccine teaches your immune system to attack a cell (the attacking virus).
History
When I first started this blog, in 2006, Diamyd was already one of the potential cures most advanced in the research pipeline. In 2008 they started two phase-III clinical trials in people in the honeymoon phase of T1D. If successful, these could have led to government approval. In January 2009, I considered the start of these clinical trials to be one of the "big-5" best news of the year. At that time they were also running several phase-II trials to test out Diamyd in other situations.
However, in 2011 one of the phase-III trials ended unsuccessfully ("did not meet the primary efficacy endpoint"), and in the next year, the other phase-III study was terminated. In the years after that, several of the previously started phase-II were unsuccessful, and the company started a few more studies, but again none of these were particularly successful.
Later, in 2015 the company started the DIAGNODE clinical trial which involved injecting the Diamyd treatment directly into a person's lymph nodes. Previous studies injected Diamyd right under the skin, much like insulin. Results from that study were available in 2020 and the follow on DIAGNODE-2 had results in 2021. I took a quick look at them, and they did not look successful to me. (See the details below, the trial was unsuccessful, but also included some results that gave hope.) So I never blogged on them.
Meantime, the company ran some meta analysis which pooled data from more than one of their studies. They included some genetic subtyping and the results were successful and statistically significant for some genetic types. I go into the details below. This led Diamyd to a much more optimistic view of the results, and so they started the DIAGNODE-3 clinical trial.
The DIAGNODE-3 Trial
This phase-III trial will recruit 330 people in the honeymoon phase of T1D, within 6 months of diagnosis. They will be between 12 and 29 years old and will have a specific gene called HLA DR3-DQ2.
Each patient will get three injections of Diamyd, one month apart, and also take vitamin-D for 2 months, and will be followed for 2 years. The primary end points are C-peptides and A1c. Secondary end points include time-in-range, insulin dose, and unexpected lows.
This study started recruiting in Europe in 2022, but the recent news is
that in September 2023 it started recruiting in the United
States. This is a big study, with 60 recruiting locations all over Europe and the United States. The trial has it's own web page here:
https://www.diagnode-3.com/
which includes a cool interactive map to find a clinic near you:
https://www.diagnode-3.com/Clinics.aspx
(Remember to select your country, if it starts off displaying a different country.)
Diatribe has a good article on this clinical trial as well:
https://diatribe.org/trial-investigates-promising-new-beta-cell-treatment
News Coverage: https://www.precisionmedicineonline.com/business-news/diamyd-medical-expand-phase-iii-diabetes-drug-trial-us
Clinical Trial Registry: https://clinicaltrials.gov/study/NCT05018585
Corporate Web Site: https://www.diamyd.com/
Discussion
For me, there are two areas of discussion for this clinical trial: (a) will it work, when previous research didn't, and (b) will the FDA approve it, based on successful results from this one study, or will more research be needed?
The big question is: will the current clinical trials be successful when the previous ones were unsuccessful? As far as I can see, there are two differences. The first is that for the recent studies, Diamyd is injected into a lymph node, while in the older studies it was injected under the skin, far from lymph nodes. Because the lymph nodes are part of the system that educates immune cells to attack the foreign cells, getting more Diamyd closer to them could make it more effective.
The second difference is that they are only accepting people who have the HLA DR3-DQ2 gene (technically they must "carry the HLA DR3-DQ2 haplotype"). The gene is associated with autoimmune diseases, especially T1D, and it is involved in synthesizing GABA, so again, it makes sense that people with this gene would be more sensitive to the Diamyd treatment. About half the people with T1D have this gene.
Are these differences enough to create success? The obvious way to measure this is to look at the phase-II DIAGNODE-2 study, which was published here:
https://diabetesjournals.org/care/article/44/7/1604/138800/Intralymphatic-Glutamic-Acid-Decarboxylase-With
https://academic.oup.com/jcem/article/107/9/2644/6602344
Unfortunately, the data is not clear. This study recruited enough people to run the analysis in a statistically significant way looking at the whole population, but when it was designed the impact of the HLA DR3-DQ2 gene was not known. After the study started a meta-analysis combining past studies suggested that people with the HLA DR3-DQ2 were much more likely to be helped by the treatment. So the researchers added a HLA DR3-DQ2 analysis to the study while it was underway and still blinded, but they did not enlarge the study. Once the study finished, they did their analysis separately: once for everyone and again for people with the HLA DR3-DQ2 gene. Sure enough, the study was unsuccessful when everyone was analyzed together. But when just the HLA DR3-DQ2 people were analyzed, the treated group did better than the untreated group. However, it was not statistically significant. There were not enough people with that gene in the study to get a statistically significant result.
In summary, we have three pieces of data:
- The phase-II study as a whole was unsuccessful.
- The phase-II study looking just at the one genetype suggests success, but is not big enough to be sure.
- A meta analysis combining previous studies was successful for the genetype.
The phase-III trial is only enrolling people with the HLA DR3-DQ2 gene, and is enrolling more people. So I do expect a clear yes or no answer from this trial.
As for the question of FDA approval, that is much simpler to answer: no one knows, but the company is optimistic and plans to submit for FDA approval if the clinical trial is successful. On paper, the FDA requires two phase-III clinical trials, and for T1D these trials involve about 300 people each. So normally, I would say they need to run another study before getting approval.
However, "in real life" (as opposed to the "on paper" requirements) the FDA did approve Teplizumab, which did not have two phase-III studies. Instead, it had one phase-III and several older studies. And Diamyd has a phase-III study and even more older studies than Teplizumab had. Diamyd has a long history of safety in previous clinical trials, something like 15 trials covering over 1000 people. Finally, Diamyd already has an orphan drug designation from the US FDA, and the company believes that will help get approval.
But no one except the FDA knows for sure what will happen if it were submitted for approval based on the phase-III trial currently underway. The path to approval is clear: Complete the clinical trial, get a successful result, submit for approval, and then it is in the hands of the US FDA.
Diamyd More Generally
https://clinicaltrials.gov/study/NCT02464033 Diamyd, Vitamin D, Vitamin D, and Etanercept
https://clinicaltrials.gov/study/NCT01122446 For at-risk people, not honeymooners.
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