Monday, June 14, 2021

Reports of the Death of Diamyd's T1D Intervention Have Been Greatly Exaggerated

Remember Diamyd Medical?  I wrote about the company and even interviewed one of the company execs (Peter Zerhouni, who was then Director of Business Development) back in 2010 (see that post at A year later, I wrote another post about it not being dead yet (see, but it later appeared to actually be dead, and I basically lost interest.

As it turns out, the Swedish biotech firm known as Diamyd Medical isn't dead after all! Diamyd Medical was founded by the Swedish entrepreneur Anders Essen-Möller when his daughter was diagnosed with Type 1 diabetes. After a failure to meet clinical endpoints many had presumed that Diamyd Medical was, for all practical purposes, dead. But as American author Mark Twain once said "Reports of My Death Have Been Greatly Exaggerated" (meaning he wasn't really dead). Evidently, the same can be said for Diamyd Medical.

The company's Type 1 diabetes vaccine Diamyd is, scientifically speaking, glutamic acid decarboxylase, but most people just refer to that by the acronym GAD. GAD is an enzyme which plays several roles in the human body, including in the brain and the pancreas. As an enzyme, it converts the excitatory amino acid known as glutamate into the inhibitory neurotransmitter GABA, which cells use to communicate. But it also has a less helpful role as an autoantigen (an element of self that provokes the generation of antibodies, or a process whereby the body's immune system attacks the body it is supposed to protect) in autoimmune Type 1 diabetes. 

Most people with Type 1 diabetes also have antibodies to GAD. But the most interesting of GAD's attributes is that when it is given as a therapeutic, it seems to interrupt the immune system's attacking of the beta cells in the pancreas, although we now know from earlier clinical trials that it only seems to work in certain people. More specifically, in newly diagnosed people with Type 1 diabetes with specific HLA haplotypes (aka genotypes).

There is another particular example worthy of mention in this dialogue because it ended up being a similar story. Another once-promising Type 1 diabetes cure-like treatment designed to arrest the autoimmune process which causes the Type 1 diabetes disease to occur, specifically the humanized anti-CD3 monoclonal antibody known as teplizumab, was also presumed dead. Insulin giant Lilly made an investment in a Maryland-based company named Macrogenics thinking that the candidate known as teplizumab would be an imminent blockbuster. But when teplizumab bombed out in clinical trials, Lilly (and its cash) disappeared. Lilly concluded it did not have a potential blockbuster on its hands, so it cut its losses and exited.

Both are relevant because both treatments failed in widespread human clinical trials, but the underlying science revealed in those trials that the treatments worked in certain patients, just not everyone. As it turns out, neither Diamyd nor teplizumab are really dead after all. Teplizumab has changed hands more than a few times, and today it is being pursued by a New Jersey-based company known as Provention Bio, Inc. which is working on bringing that treatment to commercialization. It was originally a Maryland-based biotech firm known as Macrogenics working on it, then Lilly came in with cash for large clinical trials, but when the trial result failed to meet its pre-defined milestones, Lilly and its cash disappeared. 

There are very close parallels between the two, but I've talked enough about Teplimuzab. That's a story for another day and I probably won't be telling it. Today, I'm talking about Diamyd Medical. The company is different in that it retained ownership of the intellectual property, whereas teplizumab was sold, dumped, and picked up by another company, while Diamyd Medical's intellectual property assets have stayed in the same hands all along.

Like Teplimuzab and Lilly's abandonment of that particular treatment, Diamyd Medical originally attracted major investment from J&J's Janssen unit, which entered the picture in Phase 3. But after a large-scale clinical trial failed to meet a clinical milestone, J&J exited fast. The main difference seems to be that Lilly and J&J both marched in with big money to do large clinical trials, but then both skipped town when the milestones were not met.

Diamyd Medical has endured because the company is driven by its founder's desire to see his daughter with T1D (and now a granddaughter too) cured which is touching. That said, sometimes that's not enough to bring back a failed treatment to life. But Diamyd Medical seems to be defying the odds because of the underlying science which, in spite of failing to become a mass-market cure actually DID work — just in certain subgroups of patients.  It doesn't seem to work for everyone with Type 1 diabetes, but did work for some, about half of all newly diagnosed Type 1 diabetes patients, and for those lucky patients, it might be the difference between a lifetime of ever-rising prices for insulin and all the other supplies (CGM sensors, test strips, syringes or pen needles, insulin pumps, infusion sets and all the other stuff that goes with it which lines the pockets of diabusiness).

But neither Diamyd Medical nor the developer of teplizumab were complete failures, but the big drug companies were expecting a blockbuster to come from their initial investment. But, as it turned out, both treatments appear to work in more-narrowly defined populations. 

The bright spot seems to be that the original J&J investment in Diamyd Medical wasn't a complete bust, because it proved in a very large clinical trial that the Diamyd GAD vaccine was safe. In addition, the clinical trial provided the company with valuable data that turned out to be instrumental for its future. More specifically, in 2019 an analysis of data from more than 500 individual patients that had participated in previous clinical trials showed that the genetic profile of the individual significantly influences the effect of the vaccine. These new findings were incorporated into the ongoing Phase 2b clinical trial and when the results were released in the autumn of 2020, they showed that the GAD vaccine indeed seems to work in individuals that carry the HLA DR3-DQ2 haplotype (which can be up to 50% of all Type 1's). The upcoming Phase III Diamyd 'DIAGNODE' Trial starting up in the coming months here in the U.S. and Europe will answer that. 

Big pharma investments from Lilly, J&J or others often means the death of a promising intervention when it fails to deliver widespread efficacy for the masses in clinical trials. But closer examination of the underlying data may reveal that the treatments MAY work after all in smaller groups with more precise defining characteristics. Call it precision medicine on the cure front. 

The lesson seems to be that it's possible we may yet see different T1D "cures" (even if they are not permanent, a periodic treatment with an intervention seems a decent price to pay for fully-functional Islets of Langerhans because anyone with T1D knows what life is like living with the disease, including some not-so-fun side-effects such as hypoglycemia unawareness caused by defective counter-regulatory response to imprecise insulin dosages which comes with all insulin replacement therapy because dosing insulin is assuredly not precision medicine) which either extend the honeymoon period for a much longer period, or may even do so indefinitely with ongoing treatments. As I said, it would seem that a periodic treatment with Diamyd (or teplizumab) might be preferable to multiple daily treatments with insulin and endless testing to ensure the dosages are correct since insulin replacement therapy is deeply-flawed in spite of whatever improvements pharma likes to claim. As long as dosages of insulin remain best estimates instead of precision dosages based upon plasma blood glucose levels, insulin replacement therapy will remain a deeply imprecise dosage requirement.

So, its worth staying tuned to Diamyd see what happens next on the horizon with a new trial set to begin soon. This is one of a number of trials available to those newly-diagnosed with Type 1 diabetes — and remains an opportunity to intercede in the disease process early on. As a side note, Diamyd Medical also has another interesting product now in development, called Remygen, which may make a difference for those of us who have been living with T1D for more years than we care to remember. It is being tested for its' ability to regenerate beta cells. You can check that out, and more, on Diamyd Medical's website:

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