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Clinical Trials

The Wildly Unlikely Return of TGN1412

You may be familiar with the bizarre story of TGN1412, an immunotherapy developed (briefly) by a small German company called TeGenero in 2006. This led to the infamous Phase I incident in England where a set of six volunteers were dosed at fifteen-minute intervals, but right after the last one got the injection, the first one collapsed. And then the second, and then the third. . .it was a long morning at the office, that’s for sure. Everyone involved ended up in intensive care for some time, and although none of the six died, it was clearly a very near thing.

This incident pretty much rang down the curtain on TeGenero and on TGN1412, as well it might. I remember thinking at the time that we’d never hear about it again, except as a vivid case of How Not to Do It. But an alert reader spotting this in the British Medical Journal, from back in April: TGN1412 is about to go back into humans as a potential arthritis therapy. I never would have believed it. Here’s a story from Reuters to the same effect.

The key seems to be better in vitro tests to predict such “cytokine storm” reactions. The compound is now being dosed at about 20x less than the TeGenero incident, and throttling back to about 5% seems to bring things back into a zone of safety, while still providing immune effects. (Keep in mind that even the original TeGenero dose was calculated to be far below a therapeutic one, based on what was known at the time – it’s a good thing that they didn’t try anything higher, or no one would have made it as far as the back of the ambulance). This time, Phase I trials appear to have been successful, and Phase II enrollment is going on for what’s now been renamed TAB08 (from TheraMab, the Russian/German firm that bought the rights from the bankrupt TeGenero).

If this works, it’s going to be an extraordinary story, and a real triumph of pharmacology (from what was a disaster of clinical research). An active compound – and boy, this one certainly is that – can, with enough work behind it, find a way.

19 comments on “The Wildly Unlikely Return of TGN1412”

  1. hypnos says:

    Sounds like someone is going to get a “balls of steel” award. I wonder what they told their volunteers in the informed consent form. Nevertheless, its an exciting area and we can certainly use any great drug we can get …

  2. steve says:

    Not that unusual a story – thalidomide has now been approved for multiple myeloma. How many other drugs have failed due to tox that could be repurposed for other indications and/or by modifying dose and schedule?

    1. JT says:

      With all due respect to the horrendous results of thalidomide – these were investigated and found to be due to pregnant women taking the drug within a rather narrow time frame. It has a bad reputation.
      TGN1412 had terrible side effects, and acted within a stunningly short time frame on clinical trail volunteers, so I think @hypnos is correct when he says whomever is persevering with the drug deserves ‘balls of steel’. Not to mention the volunteers…..

  3. Kumar says:

    If Celgene can bring back one of the most notorious drugs in history, thalidomide, and turn it into a successful drug for multiple myeloma, bringing back TGN1412 is not that terrible. It is definitely opportunistic and potentially lucrative considering that immunotherapy based on RIG-I, NOD agonists, STING ligands, TLR7 activation and all powerful CAR-T technology are all at the front and center of biotech activities and deal making. All these approaches have the potential for unleashing ‘cytokine storm,’ yet every major players are either pursuing them or trying to have stake in them. Yes, if this works that would be an amazing story.

  4. Chrispy says:

    sola dosis facit venenum…

    In many ways, TGN1412 has been derisked. We KNOW it has activity.

    It is interesting that a drug with such potent inflammatory effects is being developed as an anti-inflammatory (as, I believe, TGN-1412 was originally intended.). It has been a while since I looked at these patents — the last time I did they’d been abandoned. I wonder what kind of IP TheraMab was able to secure?

  5. Spike says:

    The BMJ article was summarizing an editorial from Br J Clin Pharmacol. I would recommend reading that article closely. Let’s just say that there are some inaccuracies in the article and wasn’t proof-read as well as it could be.

  6. Anon says:

    I wonder how they fast (or slowly) they will recruit patients. Well I’m certainly not volunteering for this one!

  7. Anonymous BMS Researcher says:

    I’d sure like to see their informed consent documents!

    “The first six humans to get this nearly died but we think we have found a safe dose now…”

  8. Nick K says:

    Several of the unfortunate volunteers in the first trial of TGN-1412 lost fingers and toes due to the cytokine storm.

  9. JIA says:

    Derek, this drug is not “about to go back into humans”, it has already done so, in healthy volunteers. In fact you mention “successful Phase I”, which was reported in 2014 (PubMed link in my handle), or clinical trials ID NCT01885624. They dosed 24 healthy volunteers in a single-ascending dose study. What appears to be new and about to start, is the trial in RA patients.

  10. Mark Thorson says:

    Chrispy, I’m not an expert on pharmaceutical patent law, but I believe if they can demonstrate its utility as a therapy for RA, they can obtain a use patent on TGN1412. If TGN1412 were already available to treat some other condition, you’d have a hard time preventing doctors from violating your patent and prescribing that dosage form off-label, but TGN1412 doesn’t currently have any such other uses.

  11. steve says:

    There needs to be some perspective on what happened with TGN1412. It was a rare reaction to a particular form of a CD28 superagonist. It had undergone preclinical studies in cynos and rhesus at much higher doses before going into humans. Other superagonist antibodies had gone into clinical testing without the same adverse effects. As it turned out, the company did two things wrong. First, it incorrectly assumed that primate CD28 receptors were 100% identical to human; this was wrong (there’s a 4% difference especially in one loop) and is why it was safe in primates but caused cytokine storms in humans. Second, they rapidly treated 6 patients in a row rather than one at a time while waiting to look for adverse effects. The toxicity of TGN1412 is pretty well understood now and if EMA is allowing it in trials for RA then the company must have made a pretty strong argument.

    The new application in RA appears to be due to the observation that TGN1412 activates regulatory T cells (Tregs). My guess is that this would be the basis of any new IP governing its use. However, a use patent is generally considered to be relatively weak and it’ll be interesting to see if the company (a German-Russian start-up company, TheraMAB LLC) can raise money without a composition-of-matter claim to the antibody itself.

    1. Thomas Hünig says:

      I have to clarify a point Steve made. The failure of TGN1412 to trigger a CRS in cymolgus monkeys is NOT due to poor binding to cyno CD28 – in fact, binding is identical in humans and cynos, which is due to the 100% identity of the extracellular domain (see Lessons from TGN1412. Hanke T.Lancet. 2006 Nov 4;368(9547):1569-70). The alleged differences in amino acid sequence affecting binding are a myth that was introduced into the literature based on a mis-sequenced rhesus macaque CD28.
      Rather, it was the unexpected absence of CD28 from cyno CD4 effector memory cells, the cell type which caused the CRS in humans. This subset is rare in blood but abundant in tissues. For the original data on this see: Eastwood, D. et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br. J. Pharmacol. 161, 512–526 (2010), and for a discussion: Nat Rev Immunol. 2012 Apr 10;12(5):317-8. doi: 10.1038/nri3192.The storm has cleared: lessons from the CD28 superagonist TGN1412 trial.Hünig T.

  12. gippgig says:

    Off topic but may be of interest:
    Two local PBS stations are rerunning the Frontline episode on pathogens in chicken Aug. 25 at 10PM; check your local listing.
    Nova on PBS is scheduled to be about vaccines and epidemics.
    The new site is definitely slower and sometimes won’t load at all; I’m having trouble keeping up as a result. Something should be done such as having a minimal-graphics version.

  13. NoDrugsNoJobs says:

    With respect to “IP”, the regulatory exclusivity for a new biological sequence such as a MAb is 12 years in the US and would be afforded 10 to 11 years in the EU (11 if they get a second indication).

    Since the focus on patents is generally one of exclusivity – the question then is will the innovator get enough exclusivity to justify the investment? Even in the best of cases patents will get you about 14 years (absent evergreening and switching dose forms, routes, etc). Therefore the focus in antibodies does not attach to patents to the same degree because of the long period of regulatory exclusivity in the US, provided the innovator can bring that particular and novel sequence to market first.

    In this case, it is unlikely that somebody else will pick up the exact same sequence and try to beat them to the market for RA, it would be too risky and probably a losing bet (better for them to grab their own sequence and run with that)- Also to what Steve says, there is a possibility they could get a patent to the use of the MAb provided that wasn’t described in the art elsewhere. While that would be helpful its not completely necessary for a new biological in the same way as a new small molecule. This brings us back to the patent subject brought up by Derek the other day that touched on some of the problems with patents, exclusivity and the particularities of the drug business.

  14. steve says:

    @NoDrugsNoJobs, I’m not sure what you’re referring to. You might mean that antibodies are biologics and therefore get BLA status that confers an extra 7 years of data exclusivity. However, that does not confer marker exclusivity so it does not afford the same protection as a patent. Otherwise, antibodies are not a special class of drug that get “regulatory exclusivity” because of a sequence. They can get orphan drug status depending on the indication, but that’s no different than any other drug.

  15. steve says:

    Sorry for the typo – should have read: “However, that does not confer market exclusivity…” not marker

  16. NoDrugsNoJobs says:

    Steve, you are absolutely correct, they get 12 years of data exclusivity. When thinking about exclusivity, data exclusivity is particularly important because the primary threat is a filer who can quickly follow you and not have to repeat the entire development cycle for a drug. The important thing to appreciate is that the 12 year regulatory data exclusivity afforded to a BLA is attached to the first filer only. I’m not aware of any examples where reg data exclusivity was insufficient and somebody else developed the full data package on their own and launched into the market place. The net result is that regulatory data exclusivity acts very much like market exclusivity but I stand corrected, there is a distinction though I’m not sure it makes a practical difference(or at least hasn’t yet in any circumstances I’m familiar with)

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