Uneasiness Shadows Newly Approved Drug

A Crohn’s disease drug has a troubled past — and scientists may know why.

Could the antibodies in Tysabri be causing bad reactions in patients? [Credit: Syringe, Davide Guglielmo. Antibody, David S. Godsell. Compiled by Karina Hamalainen.]
By | Posted January 30, 2008
Posted in: Featured, Health
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Though a drug once pulled from use has been approved for treating another disease, it is still generating concerns. The drug, called Tysabri, may be unpredictable in the body, according to new research. This could explain its problems in clinical trials.

Tysabri (natalizumab) is a unique way to treat people with certain types of multiple sclerosis (MS), a chronic disease that affects the brain and spinal cord. On Jan. 14, the U.S. Food and Drug Administration approved Tysabri for treatment of Crohn’s disease, a chronic inflammation of the digestive tract that causes diarrhea and abdominal pain.

A potential problem lies in what the drug is made of: tiny agents, called IgG4 antibodies, that look and act exactly the same — until entering the body. There, they may mix with our natural agents, according to research published in September 2007 in the journal Science. To prevent mixing, these agents can be stabilized. However, when asked prior to the new approval, Biogen Idec (a company teamed with Elan Corporation) would not directly say that Tysabri has been stabilized.

Rob Aalberse, an author of the Science finding and professor of immunology at the University of Amsterdam, feels that it would be scientifically interesting to determine if mixing is occurring in Tysabri. More urgently, the authors of a review of this research in the same issue of Science wrote that the possibility of harmful effects should be explored immediately in IgG4 products.

Even if Tysabri mixes unpredictably in the body, it is unclear whether this is what caused the drug’s problems in clinical trials. Tysabri was taken out of use in February 2005 after three people contracted a rare brain infection called progressive multifocal leukoencephalopathy (PML), and two of them died.

“I don’t think the Tysabri issue is related to the [mixing] IgG4 antibody,” says Lawrence Steinman, co-discoverer of Tysabri and Stanford University professor of neurology, who was not associated with the Science research. Instead, he thinks that the drug made participants susceptible to opportunistic infections like PML, and his stance has not changed since the FDA’s new approval.

Before this approval, a spokesperson for Biogen Idec said that “there’s no data that this normal [mixing] property of IgG4 antibodies is related in any way to the efficacy and safety of IgG4 products” like Tysabri.

About 400,000 people in the U.S. have MS, estimates the National Multiple Sclerosis Society. But Tysabri, which was reintroduced in the U.S. in June 2006, is intended only for people who do not respond to or cannot tolerate other treatments. The same is true for the country’s approximately 500,000 Crohn’s disease patients. Even in these cases, though, some doctors are wary about prescribing the drug.

“Other [MS drugs] have not had this kind of trouble [with PML and death]; therefore, I think it should be approached cautiously,” says Richard Pellegrino, a private-practice neurologist who specializes in treating MS in Hot Springs, Ark. Before the approval for Crohn’s, he had not prescribed Tysabri for his MS patients and estimated that over half of his colleagues were being careful.

“Most doctors will be on the cautious side,” agrees Daniel Present, who was involved in Tysabri’s clinical trials for Crohn’s disease and is a clinical professor of medicine at Mt. Sinai Medical School in New York City. Even after the FDA’s approval, he still believes that doctors will be hesitant.

Before the approval for Crohn’s, a spokesperson from the Crohn’s & Colitis Foundation of America, which lists Elan Corporation as one of its supporters, wrote in an e-mail that the foundation “takes no official position on specific treatments.”

When the National Multiple Sclerosis Society, which lists Biogen Idec as a supporter, was asked before the FDA’s approval of Tysabri about what should be done to ensure the safety of the drug based on the new research in Science, a spokesperson commented in an e-mail: “Unfortunately, it is not realistic to … ‘ensure safety.'” Instead, “one has to ‘maximize’ safety.”

To maximize safety of Tysabri, only approved pharmacies can dispense the drug, and all users are being monitored for the brain infection PML. As of late December 2007, the companies reported that there were no new confirmed cases of PML in the 21,000 users of Tysabri worldwide. However, even if caught early, PML is devastating, according to Steinman, the co-discoverer of Tysabri.

“You might prevent death, but the outcome is likely to be horrible” in terms of disability, he wrote in an e-mail prior to the FDA’s approval. Steinman still believes that “there are safer drugs for Crohn’s.”

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  1. There were only 2 people being infused with Tysabri who died of PML and in both cases Tysabri was not the culprit.

    In the case of the Crohn’s patient who died, the FDA’s Adverse Events Database clearly cites Remicade as the primary suspect. This patient was on death’s door and had been infused with azathioprine for years prior to dosing with Tysabri.

    In the case of the MS patient who died, she did not in fact have MS and had been misdiagnosed. Using Tysabri in this case was akin to applying paddles to a person who is not having a heart attack. As a result of this case, the FDA instituted the TOUCH Riskmap program that asks neurologists a number of questions to ensure that they have properly diagnosed MS and to ensure that neurologists understand the immune state of a patient prior to prescribing a therapeutic that tamps down the activity of that immune system.

    Steinman is attempting to bring competing treatments to market for autoimmune diseases and should not be cited as a credible source.

    In addition, there are 23,000 patients being infused with Tysabri right now and after almost 2 years there are zero (0) cases of PML among Tysabri users. When the risk of PML was thought to be 1 per 18,000 patient-months, the NEJM published an article pointing out that the risk of not being on Tysabri greatly outweighed the risks of the drug itself: MS progresses and causes real harm, even death.

    By contrast, investigate the incidence of death from myocardial infarction or arrythmia among beta interferon patients where Avonex, Betaseron or Rebif are cited by physicians to be the primary suspect. Does the incidence of death exceed 1:1000? Last time I checked, dead was dead regardless of cause.

    Or check the AER database for Remicade and Humira and uncover incidents where the outcome is death and either drug is the primary suspect. I bet you will see some very interesting patterns.

    Tysabri is probably the safest drug yet approved by the FDA, and perhaps, excluding antibiotics, the most efficacious. Crohns patients are very lucky to have another effective choice.

    Harold Engstrom, January 30, 2008 at 8:03 am
  2. Rachel you have a great future ahead of you as a writer for the Boston Globe. The fine editorial staff at the Boston Globe is completely comfortable with oversimplification and fear mongering. At the Boston Globe correlation and causation are synonymous and statistics should never stand in the way of a good yarn especially if the story inspires irrational fear of the unknown and leads people down the safe path of disability, blindness, or in the case of Crohn’s disease, invasive surgery and colostomy bags. Keep up the good work.

    Roger Nilsen, January 30, 2008 at 9:23 am
  3. Dear Rachel,

    You article spreads vague fears about Tysabri, but says nothing about Crohn’s Disease or Multiple Sclerosis. Be sure that both are “not likely to be horrible” but ARE ALREADY horrible, leading to disability of varying degrees and yes, even death. Let us attend to the diseases that we already have (and I have 1 of the 2), and not worry about remote fears of something else.

    Also, seeing as you are a Health journalist, I wiuld suggest that you search YouTube.com for videos of how Tysabri is creating literally miracles for people in many countries across the world.

    Sincerely,
    Pamela

    Pam Matthews, January 30, 2008 at 9:57 am
  4. In the interest of full disclosure, the article might have pointed out that:
    1. Dr. Steinman is founder of Bayhill Therapeutics, as well as the publicly traded Neurocrine Biosciences (which once had it’s own MS drug in trials). See: http://steinmanlab.stanford.edu/steinmancv.pdf (Page 4)
    2. Bayhill has an MS drug (BHT-3009) in trials and last year announced Phase 2b results for the drug. http://www.medscape.com/viewarticle/563866
    3. Bayhill is planning an IPO say the papers. http://www.bizjournals.com/sanjose/stories/2008/01/07/daily47.html?jst=s_cn_hl

    Percy Flageur, January 30, 2008 at 12:37 pm
  5. Harold said most of it quite well, with one correction. “Using Tysabri in this case was akin to applying paddles to a person who is not having a heart attack.”, this patient appeared to have had sub-clinical PML which was misdiagnosed as MS, the symptomolgy is quite similar, however the treatment is drastically different. As the patient worsened, it was attributed to an MS relapse and treated vigorously with steroids, the worst possible course of action. While Tysabri was of no help, it did nothing to hasten the patient’s demise.
    This entire article is miserably inaccurate and should be retracted.

    Ernest Kaiser, January 30, 2008 at 1:43 pm
  6. Gentlepersons,

    As a MS patient for 32 years and a Tysabri patient that has had 17 infusions of this medication so far, I feel the need to comment on this woefully inaccurate and biased article.

    For example, Ms. Mahan states the following: “Tysabri, which was reintroduced in the U.S. in June 2006, is intended only for people who do not respond to or cannot tolerate other treatments”. This statement is incorrect. See the following memorandum which issued by the FDA: “The indication in the current label states “…Tysabri is generally recommended for patients who have had an inadequate response to, or are unable to tolerate [i.e., needle phobic patients], alternative multiple sclerosis therapies.” FDA would like to clarify to the reader that the MS indication for Tysabri was carefully written by FDA and the Sponsor to indicate that its use is generally recommended for patients who have had an inadequate response to, or are unable totolerate, alternative multiple sclerosis therapies (e.g., as second-line therapy).

    However, the indication statement does not explicitly preclude the possibility of first-line therapy in some MS patients as part of the approved use. FDA recognizes that the health care provider needs to consider its use based on the unique circumstances of each patient.”

    http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf.

    Furthermore, Ms. Mahan has a propensity to quote Dr. Lawrence Steinman, (who co-discovered Tysabri/Natalizumab), and who obviously has a conflict of interest Re: Tysabri:

    1. Dr. Steinman is founder of Bayhill Therapeutics, as well as the publicly traded Neurocrine Biosciences (which once had it’s own MS drug in trials). See: http://steinmanlab.stanford.edu/steinmancv.pdf (Page 4)
    2. Bayhill has an MS drug (BHT-3009) in trials and last year announced Phase 2b results for the drug. http://www.medscape.com/viewarticle/563866
    3. Bayhill is planning an IPO say the papers. http://www.bizjournals.com/san…..st=s_cn_hl ”

    See the following Medscape article with regard to Bayhill’s MS drug which states in part: http://www.medscape.com/viewarticle/563866

    “No Clinical Impact In addition, the [BHT-3009 Phase 2] study showed no statistically significant clinical impact of lesion reduction with either dose of the vaccine. “Unfortunately, we did not see an effect on disability or relapse rates. Although the overall relapse rate was relatively low [compared with trials of other therapies], the study was not sufficiently powered to reveal such an effect. We need another, much larger phase 3 trial to answer this question,” said Dr. Garren. Headded plans are currently under way to conduct such a trial , which is expected to launch by the end of 2008.”

    In addition, Ms. Mahan relies upon Dr. Steinman’s credentials, and not the data. Obviously, even though Dr. Steinman is engrossed in a separate MS drug trial, he is correct in that one has to worry about infection, but empirically it doesn’t seem to be the horror that one could imagine. In fact, recent clinical data suggests the safety is good for reasons possibly related to the supporting science results. Who knows if Dr. Steinman even actively follows this area much any more (he could be out of date slightly and working in a different area, just because he co-discovered Tysabri doesn’t mean he has kept up with it or knows everything about it – one needs to look at data, not credentials).

    With over 21,000 MS patients currently on Tysabri therapy and no no cases of PML since its relaunch in July, 2006, the data speaks for itself with regard to its superior efficacy and safety.

    She goes on to hypothesize: “A potential problem lies in what the drug is made of: tiny agents, called IgG4 antibodies, that look and act exactly the same — until entering the body. There, they may mix with our natural agents, according to research published in September 2007 in the journal Science. To prevent mixing, these agents can be stabilized.”

    The “mixing” of FAb fragments isn’t necessarily a bad thing in that it could in some instances aid antiinflammatory activity. So, the question is: how did Ms. Mahan make the connection from the original article to discussing potential adverse effects of Tysabri?

    With respect to CD patients, Tysabri is a good alternative for people who do not tolerate or respond well to anti-TNF drugs, such as Remicade (infliximab-which was the primary suspect for the death of the CD trial patient) and Humira (adalimumab). In clinical trials, 60 percent of patients responded to Tysabri, and two-thirds of patients who were also taking steroids were able to discontinue them.

    In contrast to trials in patients with MS, results from the clinical trials of Tysabri (natalizumab) in Crohn’s disease patients have provided more encouraging data emerging emerged from the ENACT-2 trial, which suggest that Tysabri is effective in maintaining remission once an acute flare-up has been brought under control.

    Tysabri was effective in maintaining remission. Following discussions with the FDA, an additional induction trial was planned. Results of this phase III trial, called ENCORE, proved encouraging. In patients with moderate to severe Crohn’s disease and active inflammation, treatment with Tysabri met the primary endpoint (a70-point decrease in baseline CDAI score at eight and 12 weeks). Alltrial secondary endpoints, which included clinical remission (CDAIscore = 150) at both eight and 12 weeks, were also met.

    Considering the fact that patients with moderate to severe Crohn’s disease face additional surgeries to remove sections of their intestine and bowel (which in and of itself is a serious risk), Tysabri proves to be a welcome alternative to these impending surgeries not only for them, but a welcome alternative for their treating gastroenterologists as well.

    Lastly, Ms. Mahan goes on to quote Dr. Steinman as saying “Steinman still believes that “there are safer drugs for Crohn’s.”

    Considering the fact that Dr. Steinman has a nondisclosed conflict of interest which was never reported by Ms. Mahan, and she has unfairly maligned her biased opinions regarding Tysabri (Natalizumab) by placing Tysabri in a disingenuous light, she has not only performed a terrible disservice to the MS community, but to the CD community as well.

    A corrected article which is more accurate and fairly balanced should issue forthwith by Scienceline.

    Respectfully submitted,

    Lauren Roberts

    Lauren Roberts, February 5, 2008 at 2:19 pm
  7. There is an increased risk of developing PML by using Tysabri if the patient used immunosuppressive drugs. This fact is known by the FDA and by doctors also, and if I`m correct the name of these immunosuppressives are listed on the label of Tysabri.
    With the current information about the drug and by respecting the guidelines Tysabri should not cause any harmful complications.

    Best regards,
    John Snow.

    Progressive Multifocal Leukoencephalopathy, October 11, 2011 at 3:57 pm
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