Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

This week the BBC reported that a phase I clinical trial involving a monoclonal antibody experienced serious adverse events. The study, sponsored by a German biopharmaceutical company, TeGenero AG, involved TGN1412, an immunomodulatory humanized agonistic anti-CD28 monoclonal antibody that is being developed for the treatment of immunological diseases with a high unmet medical need including rheumatoid arthritis, multiple sclerosis and leukemias such as chronic lymphocytic leukemia (CLL).

Northwick_park

The healthy volunteers were testing the anti-inflammatory drug at a research unit in the grounds of Northwick Park Hospital when they suffered a reaction leading to multiple organ failure. The six men who were treated with the drug remain in intensive care after being taken ill. Two men who received the placebo injection were unaffected. Those affected apparently reported splitting headaches, vomiting and hyperventilation before fainting and being taken to the intensive care unit where they remain. The reactions took place within hours of taking the first starting dose. Four of the patients have regained consciousness and were said to be responding. The other two patients remain critically ill.

As a result of the study events, the Medicines and Healthcare products Regulatory Agency (MHRA) were investigating whether the reactions were caused by a manufacturing problem, contamination, dosing error or a completely unrelated side effect in humans.

In oncology, monoclonal antibodies (mAB’s) are created by fusing or merging a cell that produces antibodies with a cancer cell. Antibodies are the foot soldiers of the immune system. Generally, mAB’s are antagonists which prevent something from happening as shown by Genentech’s suite of products Herceptin, Rituxan and Avastin, which inhibit critical pathways (Her-2, CD20 and VEGF respectively) associated with tumours. Another example is ImClone’s Erbitux which inhibits EGF, a pathway linked to colorectal and head and neck cancers.

TGN 1412 does the exact opposite – it’s an mAB agonist that boosts or stimulates the activity of CD28, an immune system protein that is present on the surface of white blood cells. The idea behind the concept was to stimulate the immune system to fight against the disease. Antibodies are proteins in the body that target and link specific shapes (the so-called antigens) on the surface of, various cells. Humanised agonistic anti-CD28 monoclonal antibody is an antibody that binds to the T-lymphocytes. By binding these cells, it is thought that the antibody can stimulate them to attack and kill the cancer cells.

Interestingly, a recently FDA approved drug called abatacept (Orencia) from BMS, appears to actually do the opposite of TGN 1412 in rheumatoid arthritis. This drug, a selective T-cell co-stimulatory modulator, inhibits T-cell (T-lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28 indirectly. This interaction then provides a co-stimulatory signal necessary for full activation of T-lymphocytes, which have been implicated in the pathogenesis of rheumatoid arthritis. So although the T-lymphocytes are stimulated in both cases, the mechanism of action on CD28 is very different from that of TGN1412. It remains to be seen whether this is relevant to the serious adverse events that occurred this week with TeGenaro’s agent.

Tgn1412

The dramatic results of this week may lead the authorities to question whether it is appropriate and ethical to test such stimulatory drugs on healthy volunteers whose immune systems are already working effectively; it is possible that by stimulating CD28 above normal levels, it might push their immune systems into overdrive, hence increasing the risk of multi organ failure. Time will tell and it is critical that the MHRA gets the bottom of the issue expediently; it’s the very least the volunteers can expect, as well as a safe and speedy recovery.

Relevant Links:

BBC Breaking News

TeGenero AG Statement

{EDIT: A subsequent post on this topic was added 2 years later HERE}.

4 Responses to “Serious Adverse Events associated with TGN 1412”

  1. ROBERT FIDDAMAN

    MHRA – In whose Interests?
    The recent TeGenero drug trial debacle was an accident waiting to happen. As long as the Pharmaceutical Industry continues to suppress clinical trial data the MHRA (Medicines and Healthcare products Regulatory Agency) will walk blindly and feed the British public false information.
    News this week that GlaxoSmithKline knowingly withheld clinical trial data from the MHRA regarding the top selling anti-depressant drug Seroxat will add further fuel to the fire and hopefully push for an independent review into how the MHRA could be duped into believing that a drug they have reviewed on numerous occasions was safe.
    The MHRA are made up of medical experts, some of whom are former employees and shareholders of the pharmaceutical companies they grant licenses to. Surely this is wrong and at the very least there is the suspicion of a conflict of interest?
    For too long now the MHRA have been hoodwinked by the Pharmaceutical Industry. Lawsuits for damages in respect of harm caused to patients are popping up all over the place, but avoid media and public scrutiny because they are usually settled out of court on the proviso that evidence is not made public.
    A public enquiry is needed to examine how the MHRA is run and why former Pharmaceutical Industry directors are allowed onto the board. Would a convicted drink driver be allowed to adjudicate on a road safety panel?
    The MHRA need to pull the plug NOW on their close associations with the Pharmaceutical Industry. The British public expects and naively assumes impartiality and not a regulatory authority whose main interest seems to be one of ‘delivering jobs for the boys.’
    Mr Robert Fiddaman (Group Moderator of the Online Seroxat Support Group)
    Birmingham, UK

  2. Ann Godridge

    I was wondering why they used healthy volunteers for this trial? It seemed to me, as someone with an autoimmune disorder, that it would make sense to trial these kinds of remedies with people whose immune systems have the kinds of disorders that require the treatment. Especially as we know so little about how autoimmunity is triggered in the first place.

  3. John Barnes

    The blacktriangle blog has a good debate on whether the TGN1412 interim report is a whitewash.
    However, I am not sure that I agree with Rob Fiddaman’s comments that it is a question of “jobs for the boys.” There are always going to be ex-pharma industry staff in regulatory agencies, if only due to the need to hire staff who are experienced.
    The issue with ex-pharma staff in regulatory agencies is one of managing conflicts of interest, so that they are not involved with drugs or companies they may have had a previous relationship with. I think that most government departments and agencies are pretty sensitive to this.
    However, the more worrying problem, as evidenced by Vioxx and Seroxat is the lack of disclosure of negative clinical data by companies rather than lack of regulatory oversight.
    Increasingly steps are being put in place so that all clinical data is accounted for e.g. in the U.S. there is a requirement that all Investigational new drug clinical trials be listed on a database (http://www.clinicaltrials.gov).
    No system is ever going to be fail safe. The public want more effective new drugs developed, so regulators have to strike a balance between safeguarding patients interests, yet not creating a process that unduly delays approval. It is tightrope that has to be walked.

  4. Sally Church

    This is a very sad story indeed and one is only left wondering why the company thought there was a rationale for stimulating the immune system in normal healthy volunteers. As the BMJ summed succinctly it up:
    “Among the more far reaching recommendations are those that place more responsibility on sponsors and investigators to prove that it is necessary to perform a clinical trial in humans.”
    http://www.bmj.com/cgi/content/full/333/7562/270
    What happened to TeGenero? They went bust given the lack of insurance to cover the litigation and no new funds were forthcoming after the disastrous trial.
    Personally, I’m not in favour of phase I trials in normal individuals. If you take a look at cancer trials they are in cancer patients, largely because of the toxicity of the drugs being tested but playing with the immune system in homeostasis is hardly a smart approach.
    In the end, my thoughts are with the patients and their families.

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