5 April 2006

Web-Kusuri-no-Check International No8

Revised for English version of the Informed Prescriber 21 (3); 21-24, 2006

Couldn't TGN1412 Tragedy be avoided? [for health professional]

Toxic signs were ignored?
Relevant safety-predicting methods for new biological agents are needed before the first clinical trial!

Kusuri-no-Check Rokuro Hama M.D.

Six healthy volunteers who took TGN1412 for the first human trial in London on 13 March 2006 showed serious toxic reactions with collapse and loss of consciousness with multi-organ failure (MOF) and were admitted to ICU [1-3]. Three of them still need ventilator and two of the three remain unconscious and seriously ill with MOF [3]. As of 31 March 2006, four of the six patients had returned to their homes. One of the other two has been transferred out of Critical Care, and the worst-affected patient "is now fully conscious and we are encouraged by his progress" , according to a press release on the North West London Hospitals NHS Trust website [11,22].

At this moment, there appear to be several issues.

  1. TeGenero and PAREXEL say that the dose administered was one five hundredth of that produced no harm in animal but was the safety sufficiently tested?
  2. Although this trial was approved and authorized by the Medicines and Healthcare products Regulation Agency (MHRA), was examination and reporting of toxic signs in animals neglected?
  3. Are the ongoing animal tests system and interpretation methods of animal data before the first human trial sufficient?
  4. Are there any violations of the trial protocol?

What is TGN1412

TGN1412 is a superagonistic anti-CD28 monoclonal antibodies (mAb) and is also called CD28-SuperMAB[5]. Conventional anti-CD28 cannot activate T cells by itself but TGN1412 alone can activate T cells [4]. It was developed by TeGenero Immuno Therapeutics in German [5] and manufactured by Boehringer-Ingelheim [6]. TeGenero received EU-orphan drug designation for TGN1412 for the treatment of B-cell Chronic Lymphocytic Leukaemia, B-CLL in March 2005 [7].

Mechanism of action of TGN1412

  1. Superagonistic anti-CD28 mAb and its site of action

    A T cell needs two signals to become fully activated. Physiologically the "first signal" arises from T cell receptor (TCR) molecules with peptide/major histocompatibility complex (MHC) complexes on antigen presenting cells (APCs). The "second signal" is provided by the engagement of a so-called costimulatory receptor. The first to be discovered and still the most prominent of these costimulators is CD28 [4]. Binding of peptide/MHC complexes (on APCs) to TCR in vivo or binding of anti-TCR monoclonal antibodies (mAbs) to TCR in vitro produces the first signal, and binding of conventional anti-CD28 mAbs to the CD28 produces the second signal. Neither anti-TCR mAbs alone nor "conventional" anti-CD28 mAbs by themselves suffice to fully stimulate T cells, whereas a combination of both efficiently induces T cell proliferation and cytokine secretion [4].

    Superagonistic anti-CD28 antibodies such as TGN1412 and JJ316 are capable of fully activating T cells without additional stimulation of the TCR and can induce IL-2 by themselves [4]. TGN1412 is a humanized superagonistic anti-CD28 mAbs and JJ316 is a superagonistic anti-rat-CD28 mAbs.

    All the conventional anti-CD28 mAbs studied bind to a membrane-distal part of CD28, but superagonistic anti-CD28 mAbs bind to a lateral, membrane-proximal loop of the molecule (CD loop). Binding of anti-CD28 mAbs to this site leads to linear complex formation of anti-CD28 mAbs and CD28 and can stimulate T cell proliferation [4].

  2. For B-CLL

    According to the explanation by TeGenero [5], mechanism of action of TGN1412 for B cell chronic lymphatic leukemia (B-CLL) is as follows:

    Despite expressing high levels of major histocompatibility complex (MHC) class I and II molecules, CLL B-cells are ineffective antigen-presenting cells (APC). Moreover, CLL B cells tend to be resistant to activation-induced cell death, (apoptosis). It has been shown by the Company that activated T cells can induce CLL B-cells to become effective APCs, making these cells visible targets for endogenous, tumor-antigen specific T cells. In addition, TGN1412 has the potential to increase susceptibility of CLL tumor cells to induction of apoptosis.

  3. For rheumatoid arthritis

    According to the explanation by TeGenero [5], mechanism of action of TGN1412 for rheumatoid arthritis is as follows:

    A pronounced T-cell activation and expansion mediated by CD28-SuperMAB in animal models is accompanied by the expression of anti-inflammatory cytokines, like IL-10, rather than by the toxic cytokine storm of pro-inflammatory mediators induced by other agents that address the TCR complex. CD28-SuperMAB over-proportionately expand regulatory T cells, a specialized T-cell subset that suppresses auto-aggressive T-cells present in the body and which has only recently been appreciated as important guardians of immune tolerance.

    The pronounced regulatory T-cell expansion and induction of anti-inflammatory cytokines by CD28-SuperMAB are mechanistic explanations for beneficial effects of CD28-SuperMAB in animal disease models for human autoimmune/inflammatory diseases. Multiple preclinical results indicate that CD28-SuperMA are capable of inhibiting clinical signs, surrogate parameters and pathophysiological characteristics of autoimmune/inflammatory diseases in a well-tolerated fashion.

Trial methods and the clinical course
Six men spasmed in agony in the "living hell" [23]

Raste Khan who was given a placebo said in the Times Online report [9]:

"They took blood samples from everybody. Then they dosed people at two-minute intervals. Routinely five minutes after everyone had been given the drug, the first person who was given the drug started to shake. He took his top off, he looked like he was burning up, and rubbed his head. Several minutes later, it missed me and went to the third person. He started doing similar things but he vomited on several occasions. He came back to consciousness but was hyperventilating. He looked like he was in the worst pain. Then No. 4 went through similar symptoms. He took several steps and collapsed. He said 'I can't control myself. I need to use the toilet' ...Nurses had a big black liner for them to vomit in. People were fainting and coming back to consciousness. The gentleman on my left was screaming, saying his back was hurting. It was horrible. I feel guilty that I had the placebo. It was like Russian roulette. I was doing it for the money. But 2,000 is not worth your life."[9]

One of the victims, Ryan Wilson, 21, begged doctors to put him to sleep because he was in such searing agony. To sum up what his family said, his head swelled to nearly three times its normal size. His neck was the same and was wider than his head, and his skin had turned dark purple. He was likely to die after his heart, lung and kidney had failed. [10]

Well known facts before the first human clinical trial

  1. superagonistic anti-rat CD28 antibody activates CD4{T cells and CD8{T cells in vitro and severely swells lymph nodes and spleen in healthy animal in vivo.

    Treatment with 0.5mg/body/day of superagonistic anti-rat CD28 antibodyiJJ316jreportedly protected rats adjuvant arthritis [15]. However, in this animal study, no healthy rat was tested.

    On the other hand, JJ316 but not JJ319 (conventional anti-CD28 mAb) induced massive proliferation of CD4{ T cells and CD8{ T cells in vitro without T cell receptor triggering [16]. In vivo test using healthy animals in which rats received a single i.p. dose of 1 mg of anti CD mAb (JJ316 and JJ319), JJ316 treatment but not JJ319 induced marked splenomegaly and lymphadenopathy, and JJ316 but not JJ319 induced rapid and transient proliferation of most CD4 T cells (six times more) and indirectly of B cells (four times more) [16].

    Considering these experiment, superagonistic anti-CD28 mAbs for a specific animal may improve adjuvant arthritis in the animals, but on the contrary, it induced CD4{ T cells and CD8{ T cells in vitro and could induce harmful effect with single dose in healthy animals.

    Profile of effects of superagonistic anti-CD28 antibody could greatly differ between healthy and diseased animals.

  2. Half of the cancer patients in the previous studies have already suffered from the similar agent.

    According to a comment in a blog about TGN1412, half of the cancer patients have already suffered from the similar agent in the previous studies[12].

    Angus Dalgleish, a world expert on immunology, said that he was amazed the trial had been allowed to proceed. "The previous studies which caused similar severe side effects were in patients already suffering from cancer, but [the researchers] should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways," said Dalgleish, a professor of cancer at St George's hospital medical school, south London. [...] The data that should have raised the alarm were presented at a meeting of the American Society of Clinical Oncology last May. Dalgleish said an engineered antibody, developed by a team led by Steven Rosenberg at America's National Cancer Institute, and using the same pathway as TGN1412 had produced severe side effects in about half of a group of patients dying of cancer. [...]

The tragedy might have been predicted and avoided?

Severe multiple organ failure may be induced through stronger activation of helper T cells than of regulatory (suppressor) T cells inducing massive IL-2 that activate killer T cells and induction of massive cytotoxic (pro-inflammatory) cytokines (cytokine storm).

PAREXEL and TeGenero say "These events were completely unexpected." [1]. They say that TGN1412 swells the animal lymph nodes a little, but the dose administered in the clinical trial was one five hundredth of that produced no harm in animal [11-13]. "These events were completely unexpected and do not reflect the results we obtained from initial laboratory studies which enabled us to progress investigations into human volunteers ", commented Dr. Benedikte Hatz, Chief Executive Officer of TeGenero AG. "The clinical trial performed by PAREXEL adhered to standard clinical research guidelines." [14]

According to the healthy volunteer who received a placebo, administration of TGNs ended within about fifteen minutes instead of two hours according to the protocol. Two hours for 8 persons mean 15 minute for each. The second patient was administered placebo. Thus all but one should be avoided if PAREXEL adhered to the protocol strictly.

Dr David Glover, a drug industry consultant with extensive experience of antibody treatments, said the protein the drug targets may not be the same in all species. "I suspect the antibody was designed to work against human CD28 and because it was designed to work best in humans its performance in different animals may fall short of what you might have expected in humans," Glover said in an interview. "That is why the animal testing may have falsely provided reassuring results. It could be one of the explanations." [14]

Ongoing animal test system does not require to fill the gap between effects of biological products, such as humanized monoclonal antibody as TFN1412, on animal and human. More relevant methods that predict human safety and harm from animal data before the first human trial should be introduced.

However, even with current methods, it could have been predicted, to substantial extent, that humanized superagonistic anti CD28 mAb could induce harmful effect, if the animal toxicity study data and the clinical trial results of similar agent to cancer patients had been appropriately interepreted with common sense.

Serious warning to streamlining and inconsiderate promotion of clinical trial: Relevant safety-predicting methods for new biological agents are needed before the first clinical trial!

The fact that the trial was approved by the regulatory authority in UK may be a problem to be reconsidered in its own. If the event was an accident as a result of the trial conducted in a way the regulator authorized, the current standard needs to be reviewed. Conventionally, drugs are mainly chemical, but now the trend is shifting to development of biological substances. Reflecting such trend, we need to reexamine the current safety measures in which human safety is assumed based on animal test results.

Relevant safety-predicting methods for new biological agents are needed before the first clinical trial!

Moreover, it is necessary to thoroughly investigate, referring to common sense, whether current measures are appropriately followed.

In Japan, streamlining of clinical trial, including phase I trial, is urged without any established legal system to protect research subjects [17-19]. We, NPOJIP (Kusuri-no-Check) and The Informed Prescriber (TIP) submitted an opinion report in July 2005, demanding the establishment of legal system to publicly manage and monitor all trials involving human and to protect subjects for clinical trials [20]. Also we criticized the revised proposal that allowed examination of clinical trial to be inconsiderately entrusted to external body, in our opinion report (March 2006) about "proposal of partial revision of ministerial ordinance concerning the implementation standard for clinical trial of medicines that involves examination committee" [21].

This event in the UK is a strict warning against easy streamlining and promotion of clinical trial. We believe that the similar incident can also happen in Japan. We continue to monitor the conduct and regulation of clinical trials to ensure the safety of research participants. Please keep an eye on our upcoming information. The MHRA has today (5th April) released its interim report into the adverse incidents which occurred on 13th March 2006 during the clinical trials of TGN1412 (see report below) [24].

References

  1. PAREXEL (2006-03-15). Media Advisory: PAREXEL International Statement Regarding TeGenero AG Phase I Trial at Northwick Park Hospital, U.K.
  2. BBC News (2006.3.15) Six taken ill after drug trials
  3. Drugs trial men 'still improving'
  4. Beyersdorf N, Hanke T, Kerkau T, Hunig T. Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Ann Rheum Dis. 2005 Nov;64 Suppl 4:iv91-5[PubMed]
  5. TeGenero (2006-02-20). Drug Development. TeGenero.
  6. TeGenero (2003-11-17). Boehringer Ingelheim and TeGenero sign agreement to develop and@manufacture CD28-SuperMAB?.
  7. TeGenero (2005-03-13). TeGenero AG receives EU-orphan drug designation for Humanized Agonistic Anti-CD28 Monoclonal Antibody TGN1412 for the treatment of B-cell Chronic Lymphocytic Leukaemia, B-CLL.
  8. Wikipedia T helper cell
  9. Lister S., and Smith L. Doctors seek international help in treating victims March 17,2006
  10. Alex Peake,"Ryan: Spare me this pain", The Sun, 2006-03-16.
  11. TGN1412, Wikipedia, the free encyclopedia.
  12. TGN1412: round-up (March 18th, 2006) American perspectives (March 24th, 2006) Comments:
  13. Flemming N We're praying for them. 2006.3.17
  14. "Protein differences may explain drug reaction", Reuters, Sun 19 March 2006 2:39 PM GMT6.
  15. Rodriguez-Palmero M, Franch A, Castell M et al, Effective treatment of adjuvant arthritis with a stimulatory CD28-specific monoclonal antibody. J Rheumatol. 2006 Jan;33(1):110-8.[PubMed]
  16. Tacke M, Hanke G, Hanke T, Hunig T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol. 1997 Jan; 27(1):239-47.[PubMed]
  17. (in Japanese)
  18. (in Japanese)
  19. (in Japanese)
  20. (in Japanese)
  21. (in Japanese)
  22. Press Statement from Northwick Park Hospital. 31st March 2006
  23. Drugs volunteer's 'living hell' 16th March 2006.
  24. Press release of MHRA (5 April 2006):