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PostPosted: Sun Oct 08, 2006 10:59 am    Post subject: MS TREATMENTS: TYSABRI - OTHER ISSUES Reply with quote

The National MS Society is doing a couple of Webcasts in October that concern Tysabri. See:

http://msspeaks.easyphpbb.com/viewtopic.php?t=613


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PostPosted: Tue Jan 15, 2008 9:56 am    Post subject: (Article) Tysabri gets FDA OK for Crohn's disease Reply with quote

From the New York Times, January 15, 2008:

Quote:
F.D.A. Approves Drug for Intestinal Disease

By THE ASSOCIATED PRESS


WASHINGTON (AP) — Tysabri, a treatment for multiple sclerosis made by Biogen Idec and Elan, received regulatory approval on Monday for use among patients with a severe intestinal disorder.

The Food and Drug Administration approved Tysabri for use in patients with moderate to severe Crohn’s disease who do not respond to more conventional drugs, like Humira, which is made by Abbott Laboratories.

The approval represents a comeback for Tysabri, which was temporarily pulled from the market in 2005 after three patients using the drug developed a rare nervous system disorder called multifocal leukoencephalopathy.

The F.D.A. allowed the drug back on the market the following year, but only under a restricted distribution program. The drug is used by more than 12,000 multiple sclerosis patients in the United States, according to Biogen, with no new reports of the fatal disorder.

Government officials said Tuesday that Crohn’s disease patients would have to enroll in a similar distribution program for Tysabri. Patients must undergo an educational program on the drug’s risks and can receive the injectable drug only from a select group of physicians.

About 500,000 people in the United States have Crohn’s, which usually causes diarrhea, fever and internal bleeding. There is no known cure.

Biogen said distribution of Tysabri for Crohn’s patients would begin by the end of next month. Biogen said it hoped to expand Tysabri’s market to 100,000 patients by 2010, which would give the drug annual sales of $670 million.

The drug is expected to compete with Remicade, the leading Crohn’s treatment, made by Johnson & Johnson.

Shares of Biogen Idec rose 96 cents to $59.98. Shares of Elan fell 4 cents to $24.85 in after-hours trading, after rising 13 cents, to $24.89.




http://tinyurl.com/2zpdtc


Interesting that the Crohn's patients will have to be on a "restricted distribution program" like the TOUCH program currently in place for MS patients on Tysabri.
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PostPosted: Fri Jun 20, 2008 6:28 pm    Post subject: (Abstract) Cost-effectiveness analyses of Tysabri... Reply with quote

From PubMed, June 20, 2008:

Quote:
Pharmacoeconomics. 2008;26(7):617-27.

Cost-Effectiveness Analyses of Natalizumab (Tysabri((R))) Compared with Other Disease-Modifying Therapies for People with Highly Active Relapsing-Remitting Multiple Sclerosis in the UK

Gani R, Giovannoni G, Bates D, Kemball B, Hughes S, Kerrigan J.
Heron Evidence Development, Letchworth, UK.

BACKGROUND:

Natalizumab (Tysabri((R))) is a new disease-modifying therapy that has been shown to be clinically effective in patients with relapsing-remitting multiple sclerosis (RRMS) and has been licensed for use in patients with highly active RRMS (HARRMS). These patients are those who experience higher relapse rates and faster disability progression than the general RRMS population.

OBJECTIVES:

To estimate the cost effectiveness of natalizumab compared with interferon-beta, glatiramer acetate and best supportive care from various UK cost perspectives.

METHODS:

A 30-year Markov model was developed, based on previously published models for multiple sclerosis, to estimate transition between disability states and the probability of relapse within disability states. The model was parameterized with data from the UK Multiple Sclerosis (MS) Survey 2005 and data from the AFFIRM study, a 2-year multicentre, randomized, double-blind, placebo-controlled trial of natalizumab in RRMS patients. Additional data were sourced from the literature. A UK societal cost perspective was used in the base case, with additional cost perspectives considered in the sensitivity analysis. The baseline characteristics for the patient group were taken from the patient population in the AFFIRM study (mean age 36 years, mean time since diagnosis 5 years and a mean Kurtzke Extended Disability Status Scale [EDSS] score of 2.5). The model and its parameterization were designed and developed to support a reimbursement application for natalizumab submitted to the UK National Institute for Health and Clinical Excellence (NICE).

Efficacies for natalizumab and glatiramer acetate were taken from clinical trial data, and for interferon-beta from a meta-analysis of clinical trial data. Disutilities from adverse events for each comparator were also included in the model. Outcomes and costs were discounted at 3.5% per annum. Costs for interferon-beta and glatiramer acetate were based on published prices (year 2006 values) under the UK Risk Sharing Scheme, and for natalizumab the UK NHS list price was used. Diagnostic, administration and adverse event costs were also included. The incremental cost-effectiveness ratios (ICERs) were calculated for the base case, and a probabilistic sensitivity analysis was performed to assess the probability of cost effectiveness at different willingness-to-pay thresholds.

RESULTS:

The ICER for natalizumab compared with interferon-beta was £2300 per QALY. Compared with glatiramer acetate, it was £2000 per QALY, and compared with best supportive care it was £8200 per QALY. From a health and social care cost perspective, the ICERs were £18 700, £20 400 and £25 500 per QALY, respectively. At a willingness-to-pay threshold of £30 000 per QALY, the probability of natalizumab being cost effective against any comparator from a societal perspective was >89%.

CONCLUSION:

If UK society is willing to pay more than £8200 per QALY, or Health and Social Services are willing to pay more than £26 000 per QALY, this analysis suggests that natalizumab is likely to be a cost-effective treatment for all patients with HARRMS.

PMID: 18563952


http://tinyurl.com/63kcel

QALY = Quality-Adjusted Life Years

Quote:
QALY calculation
The Quality Adjusted Life Year (QALY) has been created to combine the quantity and quality of life. The basic idea of a QALY is straightforward. It takes one year of perfect health-life expectancy to be worth 1, but regards one year of less than perfect life expectancy as less than 1. Thus an intervention which results in a patient living for an additional four years rather than dying within one year, but where quality of life fell from 1 to 0.6 on the continuum will generate:-

1. 4 years extra life @ 0.6 quality of life values 2.4
2. less 1 year @ reduced quality (1 - 0.6) 0.4
3. QALYs generated by the intervention 2.0

QALYs can therefore provide an indication of the benefits gained from a variety of medical procedures in terms of quality and life and survival for the patient. Another example is shown in the figure, where treatment provides a higher area under the QALY/time curve than does no treatment.

[Figure omitted]

Value of QALYs

It is no use pretending that QALYs are anything but a crude measurement. It is necessary to be aware of their limitations - with the possibility of more research making the process more sophisticated and useful.

The use of QALYs in resource allocation decisions does mean that choices between patient groups competing for medical care are made explicit. QALYs have been criticised because there is an implication that some patients will be refused or not offered treatment for the sake of other patients and, yet such choices have been made and are being made all the time. However big the pot, choices still have to be made.



From http://tinyurl.com/5c77wd, where you can see the figure that has been omitted here.
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PostPosted: Fri Aug 01, 2008 2:08 pm    Post subject: 12 suspected PML cases being investigated Reply with quote

The 12 cases are UNCONFIRMED. This article is from TheStreet.com, August 1, 2008:

Quote:

Unconfirmed PML Cases Dent Biogen, Elan
Elizabeth Trotta
08/01/08 - 01:13 PM EDT
Senior writer Adam Feuerstein contributed to the reporting of this article.


Shares of Biogen Idec BIIB and ElanELN sank deeper Friday on investor fears that additional cases of a serious brain infection in patients taking multiple sclerosis drug Tysabri may surface in the near future.

On a conference call early Friday to discuss the two confirmed cases of progressive multifocal leukoencephalopathy (PML) tied to Tysabri treatment, Biogen Idec officials refused to disclose or discuss the number of Tysabri patients overall suspected to be afflicted with the serious and potentially fatal brain infection.

Biogen shares were sinking $18.16, or 26%, to $51.60, while Elan shares were plummeting $8.89, or 44%, to $11.16, in recent trading Friday.

There are currently 12 suspected cases of PML involving Tysabri patients detailed in the U.S. Food and Drug Administration's Adverse Event Reporting System (AERS) database.

Copies of this database information noting the suspected PML cases have circulated for weeks among some institutional investors. When Biogen reported no new PML cases on its July 22 earnings conference call, however, it appeared as if these suspected incidences of PML were false alarms.

The two confirmed PML cases announced Thursday have reignited fears that some of these other possible PML cases might also turn into the harmful disease. The fact that Biogen won't say how many suspected cases of PML exist or how many have turned out to be negative creates uncertainty as to the real incident rate of PML in Tysabri patients.

That unknown is weighing on shares of Biogen Idec and Elan.

Biogen spokeswoman Naomi Aoki declined to provide any more specifics about the suspected PML cases, stating that a "vast majority of suspected cases are not PML but are part of the [effects of] multiple sclerosis. But we don't want to get into the whole business of discussing suspected cases."

The two cases of Tysabri-related PML, disclosed in a regulatory filing Thursday, are the first confirmed reports since approval of the multiple sclerosis drug in the EU and the re-entry of the drug into the U.S. market two years ago.

The patients were on Tysabri for 17 months and 14 months, respectively. One is clinically stable and ambulatory at home and the other is hospitalized.

PML is caused by a virus that damages the white matter of the brain. In healthy people, the virus lays dormant and isn't dangerous, but it can be reactivated in people with weakened immune systems.

Tysabri was previously removed from the market after being linked to three cases of PML. The drug was subsequently relaunched with a label that warns doctors and patients about the risk of PML.

"We've said in the past, and the FDA has also said, as is clearly stated in our label that we've anticipated seeing additional cases of PML," Biogen spokeswoman Aoki said Thursday night. The label currently indicates that the expected rate is 1 occurrence in 1,000 patients, which was calculated at the time of the drug's reintroduction to the market.

According a survey conducted in October 2007, physicians indicated that they may reduce Tysabri usage by 26% in the instance of a PML case, according to Citi analyst Yaron Werber, who has a hold rating on the stock. "We thus expect slowdown in Tysabri weekly growth rate and possibly scaling back in usage. However, we believe the damage will really depend if this is the first two cases of many to come and what the true incidence will be."

As of the end of June, more than 31,800 patients were on commercial and clinical Tysabri therapy worldwide. Deutsche Bank analyst Mark Schoenebaum estimates that there are 14,000 patients who have been on the drug for more than a year. Considering there have been four PML cases observed in MS patients and one in a Crohn's disease patient, it is not in excess of the rate indicated on the label.

Still, despite the fact that PML is a known risk-factor with Tysabri, Jeffries analyst Adam Walsh, like Citi's Werber, says that a survey he's conducted suggests that two new cases of PML would lead to an abrupt and sustained decrease in Tysabri use amongst MS doctors.

The survey shows a relatively steep drop-off in Tysabri use with each additional new case of PML. This is in contrast to consensus belief that physicians will be comfortable using Tysabri so long as the rate of PML is no greater than described in the label (i.e. 1/1000), writes Walsh. The analyst has a hold rating on the stock and decreased his price target to $50 from $71.

The company said on the Friday call that its guidance for 100,000 patients on the drug by 2010 -- which Wall Street has already viewed as ambitious -- does include expected cases of PML as is indicated on its label.

"We have [the] TOUCH safety program in the U.S. and we have a risk management program in Europe, and we've done a lot of work to make sure that treating physicians know how to spot signs of it," says Aoki. "Our feeling has been that heightened clinical vigilance is the best way to monitor for PML and that certainly was the case with these two patients."

Tysabri isn't alone when it comes to instances of PML. There have been a number of other immunosuppressant drugs linked to PML, notes Summer Street's Carol Werther, including Genentech DNA and Biogen Idec's Rituxan. Also, the Food and Drug Administration issued a communication on May 29, following a review of postmarketing reports of PML in patients who took Roche's CellCept and Novartis' NVS Myfortic, drugs used to keep the body from rejecting transplant organs.

Meanwhile, as Elan and Biogen got hammered further Friday, shares of Teva Pharmaceutical TEVA -- which markets Copaxone, an MS drug with a different mechanism of action from Tysabri -- got a nice boost, climbing $1.49, or 3.3%, to $46.22 in recent trading Friday.

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PostPosted: Tue Aug 05, 2008 4:31 pm    Post subject: Update from MSN Money Market Report Reply with quote

Quote:
Market Report (BIIB)August 5, 2008 9:40 AM ET


Biogen Idec . Target $59 to $48. UBS cuts their tgt on BIIB to $48 from $59. Firm says that with the two reported PML cases in Tysabri patients occurring in less than 2 years (with one patient previously naive to MS treatment), and the increase in the number of patients receiving Tysabri therapy, firm believes the risk of additional PML cases is now more prominent. Further, they believe previous Tysabri adoption trends are not likely to continue, as clinicians and patients reassess the risk/benefit profile of the product. Firm is lowering their WW Tysabri sales est based on the weighted average of firm's 3 scenarios. They now est WW Tysabri sales of $796 mln in 2008 vs. $815 mln previously, growing to $1.035 bln in 2011, vs. $1.520 bln previously.


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PostPosted: Tue Aug 26, 2008 1:26 pm    Post subject: Article on the Tysabri situation in Forbes magazine Reply with quote

Excerpted from Forbes, August 26, 2008. I've removed sections about another Elan drug which is for Alzheimer's disease. Emphasis added.

Quote:
Adviser Soapbox
Elan: Down But Not Out
Ken Kam, Marketocracy Marketscope 08.26.08, 1:50 PM ET


...
[On] July 31, Elan and Biogen Idec announced that there were two new cases of progressive multifocal leukoencephalopathy, or PML, with patients on their multiple sclerosis drug, Tysabri. Elan’s stock dropped another 40% in after-hours trading. In just three days, Elan dropped from $33.75 to close at $9.93, down over 70%.

...
[A} big drop for Elan came on July 31 after the market closed. Two new cases of PML, a brain disease, were announced to have appeared among multiple sclerosis patients taking Tysabri. Investors suffering from deja vu shot first, and many didn’t even ask questions later.

It is understandable that the uncertainty of another PML case has led to the fear that Tysabri might be pulled from the market again or that MS patients may decide not to take Tysabri, so investors sold. I think there is a strong case that instead, this is a great buying opportunity to invest in Tysabri, again.

In 2005, Elan took Tysabri off the market when three patients came down with PML, and two died. The stock dropped from $26.90 to $8 overnight and then fell to $3 over the coming weeks, losing 90% of its value. Shareholders who went through that experience will never forget it.

That’s when Elan came on my radar screen. Two of our mFOLIO Masters, Chris Rees and Jack Weyland, started buying Elan as it dropped to $9 and continued buying as it dropped to $3 (that’s a loss of over a 60%), making Elan the largest position in their portfolios. So, I started doing research, leveraging the Marketocracy community.

I heard from countless multiple sclerosis patients and care-givers that even if Tysabri carried a 1 in 1,000 chance of death from PML, nearly all of them would accept that risk in order to get the improved efficacy Tysabri offers. MS patients on Tysabri have between 33% and 50% fewer relapses than patients on other drugs. I started buying our Elan position about three months after the drop at $7.

Tysabri came back onto the market with Food and Drug Administration Approval approval in 2006 with very explicit warning of the risks of PML and programs meant to warn and monitor for PML. Since then, more than 31,000 MS patients have accepted the 1 in 1000 risk of contracting PML that is already printed on the FDA-approved label and used Tysabri. About 14,000 have been on the drug now for more than a year.

Even with the two new cases of PML, the actual risk appears to be lower than expected. The risk may be closer to 1 out of 5,000 instead of 1 out of 1,000. But more importantly, contracting PML may no longer be a death sentence. Both of the new PML patients are alive after receiving transfusions. One is already back home, and the other is expected to be going home soon also.

I don’t think there is much of a chance of Tysabri being pulled unless the incidence of PML is greater than 1 in 1,000. And even then, if PML can be treated, I think MS patients and the FDA would be even more willing to accept the risk in order to have fewer relapses.

Since the risk of getting PML has shown to be lower than MS patients have been told to expect, and the consequences are less severe, the all important risk-reward trade off that multiple sclerosis patients have to make has actually improved in favor of Tysabri--not against it. And in the end, it is the MS patients’ use of Tysabri that will determine the value of Elan--not my opinion, nor the opinion of Wall Street analysts or journalists.

Because of Elan, it was a tough three days for my Core and Explore Portfolios. I am not expecting a quick bounce but a great opportunity to invest. The primary question going forward is whether this new information on the risks of PML causes MS patients to change their behavior and use Tysabri less or even more. We’ll all know more when Elan announces results at the end of the quarter.

In the meantime, I welcome any feedback or insights you can provide, especially if you’re from the MS community. Based on the data so far, if you conclude, like me, that MS patients will continue to use Tysabri, then this is a great opportunity to invest in a potential Elan double just as a Tysabri redo.
...

---------------
Excerpted from the August issue of Marketocracy Marketscope.


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PostPosted: Tue Aug 26, 2008 6:18 pm    Post subject: Reply with quote

That verifies what my MS neuro told me last Friday. He said that even with the two new cases, the risk is no worse than it was when it returned to market.

Btw, he isn't a fan of Biogen, but he was very involved in the Tysabri trials. He doesn't like their tactics sometimes but he admits they have some very good medicines. He likes the company that makes Copaxone the best (drawing a blank at the name.)
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Ewizabeth
DX 01/28/03 RRMS
Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Tue Aug 26, 2008 6:22 pm    Post subject: Reply with quote

Teva Neuroscience? I should know the name--I receive things in the mail from them very often.
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PostPosted: Tue Aug 26, 2008 6:24 pm    Post subject: Reply with quote

agate wrote:
Teva Neuroscience? I should know the name--I receive things in the mail from them very often.


Yes, that's it. I should have remembered since I used to take Copaxone.
He thinks they have high ethics for a drug company and he has great respect for them.

I expect if anything ever happened and I had to stop the Tysabri, I'd probably be back on Copaxone.
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Ewizabeth
DX 01/28/03 RRMS
Formerly Avonex, Rebif & Copaxone
Tysabri 06/07 through 09/09
On Copaxone again since 12/09 and hoping for oral meds to come out!
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PostPosted: Tue Aug 26, 2008 6:30 pm    Post subject: Reply with quote

That's really encouraging to know. I've been very happy with the way Shared Solutions helps me with information whenever I ask. And whenever I've needed anything, they send it to me with lightning speed.
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PostPosted: Fri Sep 19, 2008 12:08 pm    Post subject: Reply with quote

From Bloomberg.com, September 19, 2008. I've emphasized the part that was new to me.

Quote:
Elan Rises on Survey Showing MS Drug Sales Won't Fall (Update1)

By Trista Kelley

Sept. 19 (Bloomberg) -- Elan Corp. gained 5.7 percent in Dublin trading after a survey showed two cases of a deadly brain infection linked to the Tysabri multiple sclerosis treatment probably won't wipe out sales of the drug.

Ireland's largest drugmaker rose 41 cents to 7.64 euros, the most in three weeks. Sanford C. Bernstein analysts told investors today that sales of Tysabri were ``unlikely to substantially decline'' after the cases were reported on July 31. The analysts based their comments on a physician survey they conducted.

The Dublin-based company and U.S. partner Biogen Idec Inc. said in July that two people taking Tysabri as their sole medicine for MS developed the rare brain infection. In June 2006, the treatment was cleared in Europe and reintroduced in the U.S. after Elan and Cambridge, Massachusetts-based Biogen created a plan to limit the side effect. The product's label warns that 1 in 1,000 users can be expected to develop the disorder, called progressive multifocal leukoencephalopathy.

``Use is unlikely to substantially decline and may continue growing at a slower rate,'' the analysts, including Tim Anderson, wrote in a note to investors today. ``What we do not anticipate, at this stage, is a wholesale drop-off in use of Tysabri.''

The survey responses ``indicate that physicians are relatively comfortable with two cases, and could be comfortable with up to five or six cases, at least as far as their use in current patients goes,'' the analysts said.

To contact the reporters on this story: Trista Kelley in London at tkelley2@bloomberg.net.










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PostPosted: Thu Oct 23, 2008 10:43 pm    Post subject: (Article) Sale of Elan's drug delivery unit postponed Reply with quote

There's been quite a flurry of articles about how well Biogen/Idec and Elan are doing as far as their sales go, in spite of the two new cases of PML with Tysabri. Here is one of the less optimistic pieces, which has a somewhat disturbing comment about one of the patients with PML:

Quote:
Elan to decide on $300m new plant as revenue rises

By John Mulligan


Friday October 24 2008

Irish pharmaceutical firm Elan will make a decision before Christmas on the proposed location in Dublin for a $300m manufacturing plant, according to chief executive Kelly Martin.

Speaking yesterday as the company announced a 53pc year-on-year rise in revenue during the third quarter to $270.1m, Mr Martin confirmed that the planned sale of the company's drug delivery unit has been postponed "for the foreseeable future".

Elan's shares tumbled more than 9pc in Dublin yesterday to close at €5.64.

It had been expected that the drug technology unit could attract a purchase price of up to $1.4bn.

Chief financial officer Shane Cooke said there had been "considerable interest" in the unit, but that a decision had been made to pull the sale. He said structures would be put in place to fuel growth at the drug delivery division.

Private Equity

Private equity giants including Texas Pacific, Bain Capital and Warburg Pincus had all expressed an interest in the business. Kohlberg Kravis Roberts and Cinven had already pulled out of the bidding process.

Mr Martin added that the planned sale "wasn't a balance sheet reason; it was a strategic reason" when asked how the postponement might affect its ability to repay $1.1bn of debt that matures in November 2011.

He added that it would be premature to say what options the company would explore in relation to the debt.

Elan said that its adjusted earnings before interest, tax, depreciation and amortisation were now close to break-even, and that the break-even position should be achieved by year-end.

It posted a net loss of $84m for the period, down from $87m a year ago, beating estimates.

Patient enrolment for use of Elan's Tysabri multiple sclerosis treatment declined after two new cases of the life-threatening brain disease PML were discovered during the summer. One of those patients has almost recovered, while the other was "not in good shape", according to Mr Martin.

CFO Shane Cooke added that extrapolating patient enrolments since the summer, Elan would have 60,000 people using the drug by the end of 2010. That's below the 100,000 target the company hopes to reach. For every 10,000 patients that sign up to use Tysabri, Elan generates an extra $100m in annual profits.

Moderation

"There was a moderation in subscribing habits," conceded Mr Cooke, who added that it was too early to determine whether the slower take-up since the summer would continue. He added that the 100,000 target remained appropriate.

Analyst Ian Hunter with Goodbody Stockbrokers also said that the fact Tysabri subscriptions had not fallen as much as expected was a "positive riposte" to those who believed the enrolment numbers would shrink more significantly.

- John Mulligan



from independent.ie
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PostPosted: Mon Apr 06, 2009 11:41 am    Post subject: (Article) FDA cracks down on search-engine ads for Tysabri Reply with quote

From FiercePharma, April 6, 2009:

Quote:
FDA cracks down on search-engine ads

By Tracy Staton

Everybody knows Internet advertising is hot. Traditional media is watching its share of ad dollars decline again and again. Meanwhile, the digital domain's share is growing. Right now, pharma has between 5 percent and 10 percent of their marketing budgets in digital, and the share is growing, DMNews notes.

But Internet advertising has its pitfalls. Lately, FDA has cited a series of drugmakers for online video that didn't weigh in heavily enough on the side effects and risks of drugs. And now the agency is cracking down on search engine ads. You know, the briefer-than-brief liners that pop up when you google "migraine" or "congestive heart failure" or "insomnia."

Fourteen companies, including Biogen Idec, Pfizer, Sanofi-Aventis, GlaxoSmithKline, Roche--basically a who's who of pharma--got warning letters from the FDA about those "sponsored links." There's not much room to maneuver in that sort of space, as you know. And the links are just that--they go to the advertised drug's website where plenty of information is available. But still, FDA didn't like the fact that Biogen's Tysabri search engine ads--e.g., "A Multiple Sclerosis Treatment That's Different from the Others"--didn't mention the drug's connection to the potentially fatal brain infection PML. And FDA thinks Sanofi's search links "misleadingly suggest Plavix is safer than has been demonstrated."

This spate of warnings surely won't be the last. And it points out the pitfalls of online advertising, where the forms and approaches are quite different from the traditional 30-second TV spot or two-page magazine ad with plenty of space for fine print. Figuring out how to market effectively online--and satisfy the FDA, too: That's going to be a challenge, but one the industry has to meet, and soon.



The article can be seen here.
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PostPosted: Fri Oct 23, 2009 8:32 pm    Post subject: 23 cases of PML for MS patients on Tysabri? Reply with quote

From the San Francisco Examiner, October 23, 2009.

Interesting that this news pops up late on a Friday, when many people probably won't notice...

Quote:
Biogen, Elan shares fall as European regulators investigate Tysabri brain infection reports


Associated Press
10/23/09 8:45 AM PDT NEW YORK — Shares of Biogen Idec Inc. fell Friday as European regulators investigate reports of 23 cases of Tysabri patients with a potentially fatal brain infection.

The stock fell $2.54, or 5.4 percent, to $44.69 in midday trading. Shares have traded between $37.21 and $55.34 over the past 52 weeks. American depository shares of Biogen's partner, Elan Corp., fell $1.26, or 19.6 percent, to $5.17.

The multiple sclerosis drug was pulled from the market in 2005 due to concerns about the condition, called progressive multifocal leukoencephalopathy, or PML. Sales resumed in July 2006 with restrictions and a monitoring program. As of July 2009, the company had reported 11 cases of the condition and said it would stop updating reports of additional cases.

Analysts have mainly brushed off ongoing concerns of PML risks, with many saying they have already been priced into the stock. Still, some do not expect sales of the drug at the same levels they were before the PML issues.

"PML rates are exactly as we predicted in July," said Leerink Swann analyst Dr. Joshua Schimmer, in a note to investors. "If anything, our view of the Cylex assay (safety monitoring) is improving."

He called the stock's weakness Friday an "overreaction" and said double counting some patients may have pushed the actual number up too high. The true number of new patients could actually be 20, he said.

In July, Schimmer projected there would be 21 new cases from August 2009 to January 2010.

"With nine new cases, assuming 20 in total, since the end of July, we are right on track with where we should be based on the large number of Tysabri patients on therapy," he said.

Deutsche Bank-North America analyst Mark Schoenebaum said he is remaining on the sidelines until the actual number of new PML patients since July are sorted out.

"We don't think there is material risk that Tysabri is pulled from the market," he said, in a note to investors. "The reasonable risk, however, is that regulatory bodies conclude that time on drug is a risk factor for PML and recommend or mandate drug holidays."



The article can be seenhere.
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PostPosted: Sat Oct 24, 2009 12:08 pm    Post subject: Reply with quote

I think I'll call the neuro on Monday and ask him about it. My next infusion is on Friday the 30th.
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PostPosted: Sat Oct 24, 2009 2:59 pm    Post subject: Reply with quote

Well, they may not have counted right, according to the article:

Quote:
He called the stock's weakness Friday an "overreaction" and said double counting some patients may have pushed the actual number up too high. The true number of new patients could actually be 20, he said.



Even if the total is "only" 20, that's still 7 more than everybody thought.
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PostPosted: Wed Jan 20, 2010 6:45 pm    Post subject: Total number of PML cases now at 31 Reply with quote

From Boston Business Journal, January 20, 2010:

Quote:
Biogen optimistic despite more PML cases

Boston Business Journal - by Julie M. Donnelly



Biogen Idec officials said Wednesday three more patients have contracted a rare brain infection associated with the company’s multiple sclerosis drug, Tysabri.

However, the Cambridge-based biotechnology company says the additional cases do not impact the overall safety profile for the medication.

The total number of cases of progressive multifocal leukoencephalopathy, or PML, since July 2008 now stands at 31.

More than 60,000 patients have taken Tysabri since the drug’s reintroduction in July 2006, and the incidence of PML is currently .47 cases per 1,000 patients. Tysabri’s warning labels said the anticipated incidence rate of PML is 1 in 1,000 rate.

The company took Tysabri off the market between February 2005 and July 2006 because of concerns about the risk of PML.

Since the risks of contracting PML increases the longer a patient takes the drug, the number of PML cases is expected to rise. So far, 19 cases have been detected in Europe, 10 cases in the United States. Two other cases have been detected elsewhere, according to Biogen officials.




The article can be seen here.
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PostPosted: Wed Mar 17, 2010 6:31 pm    Post subject: 42 PML cases Reply with quote

The Wall Street Journal has an article stating that There are now 42 cases of Tysabri-related PML (March 17, 2010. You have to be a subscriber to read the whole article, but here is the first bit of it:



Quote:
NEW YORK (Dow Jones)--Biogen Idec Inc. (BIIB) disclosed seven more cases of a rare brain infection in multiple sclerosis patients using Tysabri, which it sells with Elan Corp. (ELN), bringing the total number of cases to 42 as of last Wednesday.

Another patient with the infection has died, bringing the ...
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PostPosted: Fri May 14, 2010 8:59 pm    Post subject: Total PML cases at 49, deaths at 11, as of May 6 Reply with quote

This is just the first paragraph of an article in the Wall Street Journal, May 14, 2010:

Quote:
Biogen: Total PML Cases At 49, Deaths At 11 As Of May 6

NEW YORK (Dow Jones)--Biogen Idec Inc. (BIIB) disclosed three more cases of a rare brain infection in multiple sclerosis patients on Tysabri, which it sells with Elan Corp. (ELN), bringing the total number of cases to 49 as of May 6.

The Cambridge, Mass., biotech company reported no additional deaths in patients that have developed progressive multifocal leukoencephalopathy, or PML, bringing the total to 11.


The total for PML cases was 46 a month ago.
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PostPosted: Fri Aug 20, 2010 5:55 pm    Post subject: Some more details about the new PML cases Reply with quote

From the Irish Examiner, August 20, 2010:

Quote:

Elan share price holds despite PML numbers

By Geoff Percival

The number of instances of rare brain disease PML in users of Tysabri (the multiple sclerosis drug co-owned by Irish pharmaceutical company, Elan) increased by five last month.


The increase, published jointly by Elan and its US partner in the drug, Biogen, brings to 63 the total number of cases reported. Thirty-five of those cases have been reported since the beginning of this year.

However, given that the number of instances still fall within the drug’s stated risk guidelines, the new numbers didn’t adversely affect Elan’s share price; which actually closed yesterday marginally up at €3.81.

"Seven months into the year, there have been 35 cases reported, averaging 5 a month. Encouragingly, the incidence rates in those upper treatment levels, which encompass significant numbers of patients, would appear to be stabilising and/or moderating," pointed out Ian Hunter of Goodbody Stockbrokers. "Having dipped in the previous month to 1.71 in a thousand, the incidence rate ticked up again this quarter, returning to 1.76 in a thousand (as in May) for patients that have received 24 or more infusions. In patients having received 30 or more infusions, the rate continued to moderate, slipping to 1.40 from 1.46 in June and 1.50 in May."

Of the latest number of cases, three are based in the US with the other two in Europe. European cases of PML among users of the drug now outweigh US instances, at 34 to date.

Elan and Biogen update on PML cases on a monthly basis; meaning that yesterday’s news — while not wholly positive — was part of a rolling newsflow, rather than a sudden announcement.

In wider news for the company, Elan recently announced that it was shelving plans to spin-off its drug delivery arm, EDT, until market conditions pick up and said that it is planning to reduce its debt levels by around 20% over the coming three years.







The article can be seen here.
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PostPosted: Sun Oct 24, 2010 6:53 pm    Post subject: (ECTRIMS) Risk perception in Tysabri-treated MS patients... Reply with quote

Presented as a poster session at the annual ECTRIMS conference in Sweden, October 14, 2010:

Quote:
Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists

I. Kleiter, F. Nguyen, N. Schäffler, J. Kasper, S. Köpke, W. Gaissmaier, C. Heesen (Regensburg, Hamburg, Berlin, DE)

Background:

Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients´ and physicians´ risk estimates and attitudes towards natalizumab treatment.

Objective:

To investigate prerequisites for informed shared decision-making on natalizumab treatment focusing on perception of risk and treatment attitude among natalizumab-treated MS patients and their neurologists.

Methods:

Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two German academic centers and in cooperating private practices were provided with an evidence-based 3-page information leaflet about natalizumab-associated PML. An evaluation sheet assessed estimates of natalizumab efficacy and PML risk as well as risk tolerance towards natalizumab therapy. Perceived severity of MS and willingness to continue natalizumab treatment were evaluated using visual analogue scales with a range of 0-10 with 10 representing the highest value.

Results:

In general, both patients and physicians overestimated natalizumab treatment effects, but patients perceived natalizumab to be more effective than physicians.

MS patients judged their disease to be more malignant than neurologists (8.5 vs. 6.5; p < 0.001) and were more likely to intend continuation of natalizumab treatment than physicians (9.0 vs. 6.1; p < 0.001). Consistently, patients were willing to accept higher risks of PML: whereas 49% of physicians would stop treatment at a PML risk of 2:10000 or lower, 83% of patients would continue at this rate (p < 0.001). Importantly, this difference could not be explained by lower risk calculation abilities or lack of understanding of patients.

Conclusion:

Coherent with risk tolerance and estimated benefits, patients were more likely to continue treatment than neurologists and they were willing to accept higher risks of PML. Information about treatment-related risks is appreciated and might support shared decision-making.









The abstract can be seen here.
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PostPosted: Mon Mar 21, 2011 5:39 pm    Post subject: (Abstr.) Tysabri markedly reduces axon damage in RRMS Reply with quote

From NTK Watch, March 21, 2011:

Quote:
Ann Neurol. 2011 Jan;69(1):83-9. doi: 10.1002/ana.22247.

Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab

Gunnarsson M, Malmeström C, Axelsson M, Sundström P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J.

Department of Neurology, Örebro University Hospital, Örebro, Göteborg.

OBJECTIVE:

The impact of present disease-modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain-specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.

METHODS:

CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second-line DMT due to breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were determined using highly sensitive in-house developed enzyme-linked immunosorbent assays.

RESULTS:

Natalizumab treatment led to a 3-fold reduction of NFL levels, from a mean value of 1,300 (standard deviation [SD], 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that found in healthy control subjects (350 ng/l; SD, 170; n = 28). Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre- and post-treatment levels of GFAP were detected.

INTERPRETATION:


Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in relapsing forms of MS. It is anticipated that highly effective anti-inflammatory treatment can reduce axonal loss, thereby preventing development of permanent neurological disability.



The abstract can be seen here.
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PostPosted: Wed Apr 13, 2011 12:30 pm    Post subject: (AAN) Risk stratification for PML in MS patients... Reply with quote

Presented at the AAN conference in Hawaii, April 9-16, 2011:

Quote:
[P03.248] Risk Stratification for Progressive Multifocal Leukoencephalopathy (PML) in MS Patients: Role of Prior Immunosuppressant Use, Natalizumab-Treatment Duration, and Anti-JCV Antibody Status

Alfred Sandrock, Cambridge, MA, Christophe Hotermans, Weggis, Belgium, Sandra Richman, Amy Natarajan, Sophia Lee, Tatiana Plavina, Gary Bloomgren, Meena Subramanyam, Carmen Bozic, Cambridge, MA

OBJECTIVE:

To assess prior immunosuppressant (IS) use and natalizumab duration as risk factors for PML in MS patients. Additionally, anti-JCV antibody status may provide another factor to better ascertain risk of PML.

BACKGROUND:

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system resulting from exposure to JC virus (JCV) and a complex interaction between other host immune and genetic factors.

DESIGN/METHODS:

Incidence of PML by prior IS use and natalizumab duration was calculated based on 63 confirmed PML patients as of August 2010, and the frequency of IS use in the TYGRIS observational study. Prevalence of anti-JCV antibody positive MS patients is estimated to be 54%.

To date, sera obtained from 20 PML patients 6.5 to 187 months prior to PML diagnosis was used to retrospectively assess the predictive value of a 2-step anti-JCV antibody assay as an additional risk stratification tool.

RESULTS:

Estimation of PML risk for patients without prior IS was 0.19 cases/1000 patients (95% CI: 0.10, 0.34) with 2 years of natalizumab, and 0.96 cases/1000 patients (95% CI: 0.59, 1.46) for patients exposed >2 years.

PML risk for patients with prior IS exposure was 0.60 cases/1000 patients (95% CI: 0.24, 1.24) with 2 years of natalizumab, and 4.98 cases/1000 patients (95% CI: 3.16, 7.46) for patients exposed for >2 years.

All 20 PML patients with pre-PML sera consistently tested positive for anti-JCV antibodies at all time points. The detection of anti-JCV antibodies in all pre-PML samples is statistically and clinically significant relative to the observed 54% seroprevalence in MS (P<0.0001).

CONCLUSIONS:

The combined effect of prior immunosuppressant use and natalizumab treatment duration identifies subpopulations of patients at lower or higher risk of developing PML. Anti-JCV antibody testing is an additional promising risk stratification tool being evaluated in ongoing studies.

Category - MS and Related Diseases: Clinical Science

Tuesday, April 12, 2011 2:00 PM

Session P03: Multiple Sclerosis: Medication Safety (2:00 pm-6:30 pm)



A little about the first author listed here, Alfred Sandrock:

Quote:
Alfred Sandrock is currently the Vice President, Clinical Development Neurology at Biogen Idec, Inc., in Cambridge, MA. Dr. Sandrock earned his PhD from the Department of Neurobiology at Harvard University and his MD from Harvard Medical School, where he serves as Assistant Clinical Professor of Neurology. He also holds a position as Clinical Associate in Neurology at Massachusetts General Hospital where he completed his residency in neurology and a fellowship in Neuromuscular Disease and Clinical Neurophysiology (EMG). Dr. Sandrock has published articles on MS, axonal regeneration, and synapse formation in journals such as Science and the New England Journal of Medicine.
In addition, while at Biogen Idec, he worked on the clinical trials of Avonex in MS, such as CHAMPS, as well as led the development of Tysabri for MS.

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PostPosted: Sun Apr 17, 2011 10:05 am    Post subject: (AAN) What happens when Tysabri is stopped? Reply with quote

Presented at the AAN conference in Hawaii, April 9-16, 2011:

Quote:
[P01.197] Natalizumab: What Happens When We Stop It?

Siobhan Kelly, Marguerite Duggan, Katie Kinsella, Christopher McGuigan, Niall Tubridy, Michael Hutchinson, Dublin, Ireland

OBJECTIVE:

To examine the outcome of patients who discontinued natalizumab treatment.

BACKGROUND:

Natalizumab is an effective treatment for highly active relapsing-remitting MS. However, increasing concern about the safety of this drug has led to treatment withdrawal in patients when perceived risks of therapy outweigh benefits or in patients who request to discontinue.

DESIGN/METHODS:

A retrospective review of all patients who stopped natalizumab examining the reason for discontinuation, average number of doses, baseline EDSS and follow up EDSS, alternative treatments and MRI evaluations after termination of therapy.

RESULTS:

Of 105 patients treated with natalizumab, five had infusion reactions. Of the remaining 100, 29 patients discontinued due to (a) physician's perceived failure of treatment (10/29) 35%( 3/10 had disability progression and 7/10 had relapses), (b) patient choice (11/29) 38%, PML 1/29 (3%) and a change in diagnosis to NMO in 1 patient. The average duration of treatment at cessation was 19 months and mean EDSS at cessation of therapy was 3.0. One patient developed PML after 40 doses of natalizumab. Following treatment withdrawal 8/29 patients (24%) relapsed. Nine (27%) patients developed new lesions on MRI (7 of these were associated with relapse).

Three patients (9%) had a large increase in disability within 6 months of stopping treatment and all had MRI scans, which showed enhancing lesions. Two of the three patients were thought to have SPMS at the time natalizumab was stopped.

Natalizumab was restarted in 6/29, alemtuzumab was given to 8/29 and rituximab was given to 2/29 patients.

CONCLUSIONS:

Discontinuation of therapy with natalizumab, even in patients who are thought to have SPMS, may lead to an increase in disease activity with increasing disability. All patients who discontinue treatment should be monitored closely for signs of disease progression and should have surveillance imaging six months after the drug is stopped.

Category - MS and Related Diseases: Clinical Science

Monday, April 11, 2011 2:00 PM

Session P01: Multiple Sclerosis: Medication Safety: Long Term Follow-up (2:00 pm-6:30 pm)



The abstract can be seen here.
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PostPosted: Tue Apr 19, 2011 5:16 pm    Post subject: (Abstr.) IRIS and the CNS Reply with quote

From PubMed, April 19, 2011:

Quote:
Curr Opin Neurol. 2011 Apr 15.

Immune reconstitution inflammatory syndrome and the central nervous system

Johnson T, Nath A.

aDepartment of Neurology, Johns Hopkins University, Baltimore, USA bSection of Infections of the Nervous System, NINDS, National Institutes of Health, Bethesda, Maryland, USA.

PURPOSE OF REVIEW:

Central nervous system-immune reconstitution inflammatory syndrome (CNS-IRIS) is a recently recognized, devastating, T-cell-mediated encephalitis that occurs in the setting of treatment of HIV infection or autoimmune diseases, the management of which remains challenging. We review the pathophysiology, the clinical subtypes and present guidelines for prevention, diagnosis and treatment of this entity.

RECENT FINDINGS:


Nearly all patients with multiple sclerosis who develop progressive multifocal leukoencephalopathy (PML) following treatment with natalizumab develop IRIS which carries a high morbidity and mortality rate. Chronic lymphocyte activation is commonly present in the CNS of HIV-infected patients despite adequate treatment with antiretroviral therapy (ART), suggesting that a chronic from of CNS-IRIS may contribute to the neurocognitive impairment in this population.

SUMMARY:

The risk for CNS-IRIS can be decreased by starting ART early in the course of the illness or by reducing antigenic burden with antimicrobial treatment for opportunistic infections prior to starting ART.

Of all the forms of CNS-IRIS, the management of IRIS associated with PML due to JC virus infection remains the most challenging, as no antimicrobial drug against this virus is available and the treatment of IRIS requires the use of corticosteroids, which impair the immune cells needed to control the infection.

PMID: 21499099


The abstract can be seen here.
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PostPosted: Wed Jun 15, 2011 10:21 am    Post subject: (Abstr.) Dramatic worsening after plasma exchange,,, Reply with quote

From PubMed, June 15, 2011:

Quote:
Mult Scler. 2011 Jun 13.

Dramatic worsening following plasma exchange in severe post-natalizumab withdrawal multiple sclerosis relapse

Papeix C, Depaz R, Tourbah A, Stankoff B, Lubetzki C.
SourceDepartment of Neurology, MS clinic, Salpêtrière Hospital, Paris, France.

We report the case of a young woman with multiple sclerosis who discontinued natalizumab twice and experienced a severe relapse following each natalizumab withdrawal.

The first relapse was successfully treated by intravenous methylprednisolone (IVMP). In contrast the second relapse was unresponsive to IVMP.

Subsequent treatment by plasma exchanges (PLEX) was followed by a dramatic neurological worsening. This case suggests that PLEX after natalizumab discontinuation may increase relapse severity.

PMID:21669937


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PostPosted: Sat Nov 05, 2011 11:50 pm    Post subject: (Abstr.) A PML under Tysabri therapy... Reply with quote

From PubMed via NTK Watch, October 26, 2011:


Quote:
J Neurol Neurosurg Psychiatry. 2011 Oct 19.

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy

Phan-Ba R, Lommers E, Tshibanda L, Calay P, Dubois B, Moonen G, Clifford D, Belachew S.
SourceDepartment of Neurology, Myelin Disorder Research Team (MYDREAM), CHU of Liege, Liège, Belgium.

Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role of MR scanning has not been investigated but holds promise since MR detection is highly sensitive for PML lesions.

The authors report a case of presymptomatic PML of the posterior fossa detected by MR scans. Immediate suspension of natalizumab and plasma exchanges resulted in a rapid decline of natalizumab serum concentration. Intravenous steroids started together with plasma exchanges followed by an oral tapering course were used to minimise the immune reconstitution inflammatory syndrome.

No symptoms (beyond mild headache) developed, and the repeat PCR for JC Virus (JCV) DNA detection performed 10 weeks later was negative.

This case suggests that: (1) periodic brain MR scans may detect signs of presymptomatic PML in MS patients treated with natalizumab, (2) corticosteroid management of inflammatory reaction may contribute to optimal control of the immune reconstitution inflammatory syndrome routinely seen with natalizumab-associated PML and (3) early radiological detection of PML can have an excellent outcome even in a clinically critical region and despite prior immunosuppressant exposure.

The potential benefit of regular MR scanning just using the T2/FLAIR modalities could be further investigated in order to detect early natalizumab-associated PML, leading to benign outcomes.

PMID:22013244
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PostPosted: Thu Nov 24, 2011 12:04 am    Post subject: Hematological side effects of Tysabri... Reply with quote

From PubMed, November 23, 2011:

Quote:
Rev Neurol (Paris). 2011 Nov 17.

[Hematological side effects of natalizumab: Correlation with clinical outcome.]

[Article in French]

Bresch S, Cohen M, Rocher F, Laffon M, Thomas P, Lebrun C.

Service de neurologie, hôpital Pasteur, 30, voie Romaine, BP 69, 06002 Nice cedex, France.

INTRODUCTION:

Natalizumab (NTZ) is a monoclonal antibody used in a single-drug regimen to treat active relapsing remitting multiple sclerosis. Safety data collected during the AFFIRM pivotal study and post marketing cohorts reported infusion-related and allergic reactions, with development of persistent anti-NTZ antibodies in 6% of patients. Occurrence of hematological side effects (HSE), such as hyperlymphocytosis (HL) and hypereosinophilia (HEo) have been described. To our knowledge, there is no study assessing neither incidence of HSE, nor their correlation with clinical outcome. The objective is to evaluate prospectively the incidence of HSE of NTZ and to search for correlations with clinical outcome.

METHODS:

Clinical (EDSS, relapse, tolerance) and biological assessments were performed before the first infusion and every month during the follow-up in all patients treated with NTZ between 2007 and 2010. Before starting NTZ, data were collected on prior history of allergy and previous disease-modifying treatments (DMT). Statistical analysis was performed to search for correlations between the occurrence of HSE and clinical outcome.

RESULTS:

The series included 66 patients (sex ratio: 1/2.8) followed for up to 17 months. Mean age was 39 (±SD) years. Mean EDSS score was 3.2 (±SD). Fifty-six percent of patients had DMT history with beta interferons (41%), glatiramer acetate (6%) and immunosuppressive drugs (cyclophosphamide, mitoxantrone) (9%). Annualized relapse rate during follow-up was 0.41. Infusion-related reactions were noted in 10% of patients. Two patients had allergic reactions and had stopped their infusions. HL developed in 48% of patients and HEo in 20%. Regarding age and medical or therapeutic history, no predictive factor of HSE occurrence could be identified. Incidence of infusion-related side effects was higher in patients with HEo (38%) in comparison with patients without HEo (3.8%). Relapse rate during NTZ treatment was not significantly different between the different groups.

CONCLUSION:

This is the first prospective study assessing of HSE during NTZ treatment. There is a higher occurrence of intolerance reactions in patients with HEo.


PMID:22100322
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PostPosted: Thu Mar 22, 2012 6:27 pm    Post subject: Severe hematological complications during Tysabri treatment Reply with quote

From Multiple Sclerosis Journal, March 21, 2012:

Quote:
Severe haematological complications during treatment with natalizumab

L Midaglia1
M Rodriguez Ruiz2
D Muñoz-García1
1Neurology Department, Complexo Hospitalario Universitario de Vigo, Spain
2Hematology Department, Complexo Hospitalario Universitario de Vigo, Spain
Luciana Midaglia, Neurology Department, Complexo Hospitalario Universitario de Vigo, Pizarro 22, 13th floor, 36204 Vigo, Spain. Email: lulimidaglia@gmail.com

The safety profile of natalizumab has been widely discussed due to several cases of progressive multifocal leukoencephalopathy, reported worldwide.

Since the launch of natalizumab, 32 patients have been treated at our centre. In this context, we describe two cases (6.25%), one of immune-mediated acute haemolytic anaemia (IAHA) and another of immune thrombocytopenic purpura during treatment with natalizumab. The temporal relationship between drug administration and the nature of the haematological complications, confirmed with the serological findings in the case of the IAHA, suggests that natalizumab is the most probable cause for these adverse events.

Although very uncommon, the haematological complications are severe enough to justify a close and careful monitoring for all patients with multiple sclerosis treated with an immunosuppressant treatment.



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PostPosted: Wed May 02, 2012 12:43 pm    Post subject: (AAN) Registry to identify PML cases w/uniform dx criteria Reply with quote

Presented at the AAN conference in New Orleans, April 21-28, 2012:

Quote:
[S08.002] Establishment of a Registry To Identify Cases of PML Using Uniform Diagnostic Criteria

Avindra Nath, Eugene Major, Bethesda, MD, Allen Aksamit, Rochester, MN, Leonard Calabrese, Cleveland, OH, James Sejvar, Decatur, GA, Camille Kotton, Boston, MA, Maria J. Barhams, Bethesda, MD

OBJECTIVE:

PML is not a nationally notifiable disease in the U.S., nor is hospital- or population-based surveillance in existence that would identify suspected cases of PML or acquire samples that would benefit future research. The Registry has been formulated to provide a mechanism to identify cases using a Steering Committee involving Neurology, Rheumatology, and Infectious disease specialists.

BACKGROUND:

While historically the highest incidence of progressive multifocal leukoencephalopathy, PML, occurs in HIV-1 infected individuals, the more recent association of PML with immunomodulatory therapies has heightened the need for reporting.

The use of natalizumab in Multiple Sclerosis shows an incidence of PML of 1:750 and in patients receiving 24 or more doses with past history of immune suppressive drugs, the incidence nears that of HIV-1 infection.

DESIGN/METHODS:

The Registry is an open, Web-based program available for use by approved clinicians that collects information on: 1) selected clinical symptoms suggestive of PML, 2) MRI data, and 3) laboratory data for the detection of JCV DNA in the CSF or from brain biopsy. These criteria are formatted using a web-based form to report information to be stored in the registry under three diagnostic categories: definite, probable, and possible.

RESULTS:

The Registry allows for voluntary submission of patient biological samples for use by researchers. In turn researchers, could request access to samples and associated data through written submissions to the Steering Committee for evaluation. Researchers would be required to publish the results of their studies.

CONCLUSIONS:

Establishment of a national PML registry will allow for standardization of clinical and diagnostic information collected on suspected PML cases, allow for a more accurate estimation of incidence and prevalence of the disease, determine secular trends of PML prevalence, and allow for a repository for biological specimens from PML cases for future research.

Category - Neurologic Manifestations of Systemic Disease: Epidemiology

Tuesday, April 24, 2012 1:15 PM

Session S08: Neurologic Manifestations of Systemic Disease (1:00 pm-2:45 PM)



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PostPosted: Tue May 22, 2012 6:02 pm    Post subject: (Abstr.) Tysabri detectable in PwMS long after treatment end Reply with quote

From Multiple Sclerosis Journal, June 2012:

Quote:
Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped

Theo Rispens1,2
Anke Vennegoor3
Gert Jan Wolbink1
Chris H Polman3
Joep Killestein3

1Sanquin Research, Amsterdam, The Netherlands
2Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands
3VU University Medical Centre, Department of Neurology (MS Centre Amsterdam), Amsterdam, The Netherlands
Dr Joep Killestein, Neurologist, VU University Medical Centre, Department of Neurology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Email: j.killestein@vumc.nl

Natalizumab is frequently used as a treatment for multiple sclerosis (MS). The occurrence of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients indicates that its prominent beneficial effects need to be balanced against the risks. Also, cessation of the drug seems to be associated with recurrence of disease activity. Both the moment of rebound disease activity and the outcome of PML are related to clearance of the drug. Specific features of this IgG4 antibody (i.e. half-antibody exchange) may result in underestimated drug levels.

Here, we demonstrate natalizumab levels in 10 patients with relapsing MS, using a recently developed sensitive assay. Remarkably, natalizumab was detectable up to 200 days after cessation of therapy.



Tysabri must have remained detectable in these patients for over 6 months.

The abstract can be seen here.
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PostPosted: Fri Aug 03, 2012 5:29 pm    Post subject: Benign disorder raises concerns about CNS lymphoma Reply with quote

From PubMed, August 3, 2012:

Quote:
Neurology. 2012 Aug 1.

CLIPPERS [Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids] complicating multiple sclerosis causing concerns of CNS lymphoma

Ortega MR, Usmani N, Parra-Herran C, Adams DJ, Steingo B, Rammohan KW.

From the University of Miami (M.R.O., N.U., D.J.A., K.W.R.), Miami, FL; Brigham and Women's Hospital (C.P.-H.), Boston, MA; and Fort Lauderdale MS Center (B.S.), Fort Lauderdale, FL.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disorder of the brainstem and cerebellum with distinct clinical and radiologic features.(1) Coexistence of CLIPPERS and multiple sclerosis (MS) has never been previously described.

We present a patient with MS who developed CLIPPERS shortly after natalizumab withdrawal, and the presentation raised concerns of primary CNS lymphoma which led to a brain biopsy.

Awareness of this benign disorder may well have averted this biopsy. Recognition of CLIPPERS is crucial when one encounters perivascular enhancing lesions of the brainstem that are atypical for MS, but typical for this disorder.

PMID:22855867


The abstract can be seen here.
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PostPosted: Wed Sep 19, 2012 10:32 pm    Post subject: ) Serum Tysabri concentration & anti-Tysabri antibodies. Reply with quote

From Multiple Sclerosis Journal, September 19, 2012:

Quote:
Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis

Anke Vennegoor1
Theo Rispens2
Eva MM Strijbis1
Alexandra Seewann1
Bernard MJ Uitdehaag1,3
Lisanne J Balk1
Frederik Barkhof4
Chris H Polman1
Gertjan Wolbink2,5
Joep Killestein1

1Department of Neurology, VU University Medical Center, The Netherlands
2Landsteiner Laboratory Sanquin Research, The Netherlands
3Department of Epidemiology and Biostatistics, VU University Medical Center, The Netherlands
4Department of Radiology, VU University Medical Center, The Netherlands
5Jan van Breemen Institute, The Netherlands
A Vennegoor, Department of Neurology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Email: a.vennegoor@vumc.nl

Background:

Antibodies against natalizumab have been found in 4.5–14.1% of natalizumab-treated multiple sclerosis (MS) patients. If antibodies persist, they are associated with an adverse effect on treatment response. However, it has proved to be difficult to standardize anti-drug antibody measurements.

Objectives:

The purpose of this study was to evaluate the clinical and radiological impact of serum natalizumab concentrations and their relation with anti-natalizumab antibodies in MS patients.

Methods:

In this prospective observational cohort study of 73 consecutive patients treated with natalizumab, we measured serum natalizumab levels and antibody titers before the start of natalizumab treatment, at weeks 12 and 24 and annually after natalizumab initiation. Antibodies against natalizumab were measured by radioimmunoassay and serum natalizumab concentrations using a newly developed enzyme linked immunosorbent assay (ELISA). Magnetic resonance imaging (MRI) scan and clinical evaluation were performed before the start of natalizumab treatment and subsequently every year.

Results:

Antibodies were detected in 58% of the natalizumab-treated patients. All patients developed their antibodies before week 24. The large majority of these patients reverted to neutralizing antibody (NAb) negative status during follow-up. The presence of antibodies was inversely correlated with serum natalizumab concentration (p<0.001). Only high antibody titers are associated with very low or undetectable serum natalizumab concentration. Both high antibody titers and low serum natalizumab concentrations are associated with relapses and gadolinium-enhancing lesions on MRI.

Conclusions:

Our data show that both low natalizumab serum concentration and high antibody titers are associated with a lack of efficacy of natalizumab. Measuring serum natalizumab, using a highly specific assay, might lead to more enhanced precision using natalizumab in individual patients.

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PostPosted: Tue Oct 02, 2012 4:37 pm    Post subject: (Abst.) Trajectory of fatigue severity ... Reply with quote

This is a small study but it looks as if some people on Tysabri find that their MS fatigue becomes worse "despite very low disease activity."

From PubMed, October 2, 2012:

Quote:
Clin Neurol Neurosurg. 2012 Sep 26. pii: S0303-8467(12)00478-7. doi: 10.1016/j.clineuro.2012.08.039.

Trajectory of fatigue severity in natalizumab-treated multiple sclerosis patients.
Yildiz M, Tettenborn B, Borgwardt S.

Department of Neurology, Kantonsspital Sankt Gallen, Saint Gallen, Switzerland. Electronic address: yildizmur@yahoo.com.

Fatigue is one of the most debilitating symptoms in multiple sclerosis (MS). The aim of this study was to observe the severity of MS-associated fatigue in a community-based sample of natalizumab (ntz) treated patients over one year.

In 48 relapsing-remitting MS patients (mean age=38.3 years) fatigue was longitudinally measured with the Modified Fatigue Impact Scale (MFIS) at two time points. The primary analysis of differences in MFIS was performed using non-parametric Wilcoxon test for dependent variables.

Mean total MFIS Score increased significantly from 32.6±20.9 to 49.1±20.0 over the observation period of 12 months (p<0.001). 83% of patients remained clinically disease activity free (no relapse, no progression in the Expanded Disability Status Scale, EDSS) over the observation period of one year. Age, gender, disease duration, spinal involvement, Gd-enhancement, depressive symptoms and EDSS had no influence on fatigue levels as measured with MFIS.

Severity of fatigue symptoms during ntz treatment might increase despite very low disease activity.


PMID:23021201


The abstract can be seen here.
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PostPosted: Fri Oct 12, 2012 1:06 pm    Post subject: ECTRIMS: Remain vigilant after Tysabri discontinuation... Reply with quote

Presented in the category "Risk Management for Disease-Modifying Treatments" at ECTRIMS in Lyon, October 12, 2012:

Quote:
Remain vigilant after natalizumab discontinuation: three remarkable cases

S. Roggerone, F. Durand-Dubief, F. Chenevier, S. Berroir, E. Creisson, A. Benoit, S. Boulogne, C. Laurencin, S. Vukusic, C. Confavreux (Bron, Annemasse, Thonon, FR)

Introduction:

Discontinuation of natalizumab (NZ) has to be considered in MS patients with high risk of Progressive Multifocal Leukoencephalopathy (PML). Neurologic conditions [that can lead to diagnosit challenges] can be observed after NZ discontinuation.

Observations:

1. A 49 year-old MS woman was treated with NZ from 2007 to April 2011. NZ was stopped after 43 infusions despite an excellent clinical response because of a JCV serology tested positive. In June 2011, she developed progressive aphasia. MRI showed atypical extension of 2 preexisting MS lesions and a new left occipital lesion, without enhancement. JCV PCR in the CSF was negative. The patient progressively developed mutism, hemiparesis and cortical blindness. In July, brain MRI showed an important worsening of lesions highly suggestive of PML. A new JCV PCR in the CSF revealed replication leading to PML diagnosis.

2. A 45 year-old man receiving NZ since 2007 developed insidious worsening in walking ability suggestive of disability progression. JCV serology tested positive. Brain MRI was stable. NZ was stopped after 24 infusions. A systematic MRI performed 3 months later revealed left occipital lesions with punctuated enhancement, atypical for MS. JCV PCR in the CSF was negative (two PCR techniques). The patient developed asthenia and visual field alteration. Following MRI revealed extension of lesions in both temporo-parietal lobes, with increasing enhancement. Four lumbar punctures failed to detect JCV (three PCR techniques). After high dose IV steroids, the patient and the MRI abnormalities steadily improved. PML remains highly suspected.

3. A 31 year-old man received NZ from 2008 to November 2010, and stopped after 35 infusions because of persisting relapses and progressive disability accumulation. In January 2011, he developed subacute apyretic confusion and paraparesis. MRI revealed extensive bilateral occipital T2 lesions with faint gadolinium enhancement atypical for MS. JCV PCR in the CSF was negative. After high dose IV steroids, the patient and MRI slowly improved. In the absence of alternate diagnosis, PML remains possible.

Discussion & Conclusion:

Development of new lesions or symptoms after NZ discontinuation requires extreme attention: MS reactivation can be confounded with PML and both have to be systematically considered. As JCV PCR sensitivity is only 80%, diagnosis might require brain biopsy. It is wise to advise systematic MRI 3 and 6 months after NZ discontinuation.

______________________________

S. Roggerone has nothing to disclose. F. Durand-Dubief has nothing to disclose. F. Chenevier has nothing to disclose. S. Berroir has nothing to disclose. E. Creisson has nothing to disclose. A. Benoit has nothing to disclose. S. Boulogne has nothing to disclose. C. Laurencin has nothing to disclose. S. Vukusic reports receiving consulting fees from Biogen Idec, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma ; lecture fees from Bayer-Schering, Biogen Idec, Merck Serono, Sanofi Aventis and Teva ; and research support from Bayer-Schering, Biogen Idec, Merck Serono, Sanofi Aventis and Teva. C. Confavreux reports receiving consulting fees from Biogen Idec, Genzyme Corporation, Novartis, Merck Serono, Sanofi Aventis, Teva Pharma and UCB Pharma ; lecture fees from Bayer-Schering, Biogen Idec, LFB, Merck Serono, Sanofi Aventis and Teva Pharma ; and research support from Bayer-Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva Pharma.










The abstract can be seen here.
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PostPosted: Wed Nov 14, 2012 9:01 am    Post subject: (Abst.) CSF parameters of B cell-related activity... Reply with quote

From NTK Watch - Today in General Medicine, November 13, 2012:

Quote:
Mult Scler. 2012 Oct 23.

Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy

Harrer A, Tumani H, Niendorf S, Lauda F, Geis C, Weishaupt A, Kleinschnitz C, Rauer S, Kuhle J, Stangel M, Weber F, Uhr M, Linnebank M, Wildemann B, Jarius S, Guger M, Ayzenberg I, Chan A, Zettl U, Wiendl H, Pilz G, Hitzl W, Weber J, Kraus J.
SourceDepartment of Neurology, Christian-Doppler-Klinik, Paracelsus Medical University, Austria.

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS.

We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy.

In a retrospective chart analysis, CSF parameters of blood-CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy.

At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients.

We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

PMID:23093485
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PostPosted: Sun Jan 27, 2013 7:16 pm    Post subject: (Abst.) Switching from Tysabri to fingolimod... Reply with quote

From PubMed via NTK Watch, January 25, 2013:

Quote:
Acta Neurol Scand. 2013 Jan 22.

Switching from natalizumab to fingolimod: an observational study

Sempere AP, Martín-Medina P, Berenguer-Ruiz L, Pérez-Carmona N, Sanchez-Perez R, Polache-Vengud J, Feliu-Rey E.

Neurology Department, Hospital General Universitario de Alicante, Alicante, Spain.

BACKGROUND:

Multiple sclerosis patients who discontinue using natalizumab are at risk of a rebound in disease activity. However, the optimal alternative therapy is not currently known.

AIMS OF THE STUDY:

We report on clinical and MRI data and patient safety in a group of relapsing-remitting multiple sclerosis patients who tested seropositive for the JC virus and who have switched from natalizumab to fingolimod because of concerns regarding PML risks.

METHODS:

The test for JC virus antibodies was performed in 18 relapsing-remitting multiple sclerosis patients who were being treated with natalizumab for more than 1 year. Eight seropositive patients switched to fingolimod while the seronegative patients continued with natalizumab.

RESULTS:

After switching to fingolimod, five of eight patients (63%) experienced clinical relapses, and MRI activity was detected in six of eight patients (75%). Neither clinical relapses nor MRI activity was observed in the patients who continued with natalizumab. No serious adverse effects were detected.

CONCLUSIONS:

Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis, but its discontinuation continues to be a complex problem. All of the therapies tried thus far, including fingolimod, have been unable to control the reactivation of the disease.

Further studies addressing alternative therapies after natalizumab discontinuation are necessary.

PMID:23336398
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PostPosted: Thu Feb 07, 2013 7:09 pm    Post subject: (Abst.) Tysabri-related reversible encephalopathy syndrome Reply with quote

From Multiple Sclerosis Journal, February 6, 2013:

Quote:
Natalizumab-associated reversible encephalopathy syndrome mimicking progressive multifocal leukoencephalopathy

Bernhard F Décard1,*
Aiden Haghikia1,2,*
Christina Tönnes1
Jan Thöne1
Carsten Lukas3
Andrew Chan1
Ralf Gold1

1Department of Neurology at St Josef-Hospital, Ruhr-University Bochum, Germany.
2Department of Clinical Neurology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK
3Department of Diagnostic and Interventional Radiology and Nuclear Medicine at St Josef-Hospital, Ruhr-University Bochum, Germany.
Bernhard F Décard, MD, Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, D-44791 Bochum, Germany. Email: b.decard@klinikum-bochum.de
↵* These authors contributed equally to this work.

Progressive multifocal leukoencephalopathy is a rare but potentially lethal adverse event in natalizumab treated multiple sclerosis patients. We report on a 40-year-old Caucasian man with typical relapsing progressive multiple sclerosis, who developed a reversible leukoencephalopathy syndrome after 43 natalizumab infusions mimicking progressive multifocal leukoencephalopathy. To our knowledge, this is the first case of its kind. Our case suggests that awareness ought to be sharpened for reversible leukoencephalopathy syndrome in the follow-up of natalizumab treated multiple sclerosis patients.

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PostPosted: Tue Mar 12, 2013 6:39 pm    Post subject: Early detection of PML may increase survival rate Reply with quote

From Ivanhoe, March 12, 2013:

Quote:
Improved Survival for MS-Related Brain Infection

(Ivanhoe Newswire) -- A drug called natalizumab is used to effectively treat multiple sclerosis (MS), but it also increases the risk of a rare potentially fatal brain infection called progressive multifocal leukoencephalopathy (PML). New research out of Biogen Idec in Weston, MA, suggests that early detection of PML may improve survival rates and disability levels.

Researchers examined 319 people with MS who were treated with natalizumab and diagnosed with PML. Due to the risk of PML, people taking the drug are monitored by their doctors for symptoms. The study compared people who had symptoms of PML at the time of diagnosis to people who did not have symptoms, but who were diagnosed with the disease by tests in the spinal fluid and brain scans for the virus that causes PML. The disability levels of participants in the study were assessed before the PML diagnosis, at the time of diagnosis, and at six months and one year after the diagnosis.

Twenty-one people had no PML symptoms at the time of their diagnosis, while 298 people had symptoms. Study author and medical director, Tuan Dong-Si, MD, suggests that the study results suggest that people who do not have any symptoms at diagnosis may have improved survival and less disability.

At the time of PML diagnosis, people who did not have any symptoms had an average score of 67 on the Karnofsky Performance Scale, which measures disability. People with symptoms had a score of 54.

A Karnofsky score of 70 indicates that the patient may be able to take care of themselves. However, they may be unable to do normal activities or do active work. A score of 50 indicates that a person may require a considerable amount of assistance and frequent medical care. One year after PML diagnosis, the average score of those patients without symptoms at diagnosis was 70, compared to 47 for those with symptoms.

As of January 1, 2013, 100 percent of participants without symptoms at time of diagnosis were living, compared to 77 percent of people with symptoms at the time of diagnosis.

“These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," Dr. Dong-Si was quoted as saying.

SOURCE: Presentation at the American Academy of Neurology, March 2013


The article can be seen here.
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PostPosted: Mon Mar 25, 2013 4:49 pm    Post subject: (AAN) Seizures in PwMS & Tysabri-related PML Reply with quote

Presented at the AAN annual conference in San Diego, March 16-23, 2013:

Quote:
[P01.186] Seizures and Preventive Antiepileptic Treatment in Patients with Multiple Sclerosis and Natalizumab Associated Progressive Multifocal Leukoencephalopathy

Robert Hoepner, Bochum, NRW, Germany, Stefanie Dahlhaus, Bochum, NRW, Germany, Susanne Kollar, Bochum, NRW, Germany, Barbara Zurawski, Bochum, NRW, Germany, Andrew Chan, Bochum, Germany, Ingo Kleiter, Bochum, Germany, Ralf Gold, Bochum, Germany, Kerstin Hellwig, Bochum, Germany

OBJECTIVE:

Seizure frequency and effectiveness of preventive antiepileptic treatment (PAT) in natalizumab associated progressive multifocal leukoencephalopathy (NAT-PML) was analyzed.

BACKGROUND:

Seizures occur in 20% of HIV associated progressive multifocal leukoencephalopathy patients and with unknown frequency NAT-PML.

DESIGN/METHODS:

We reviewed medical records of 15 NAT-PML patients (9 female, 6 male, mean duration of MS 12 SD 6.4) years, mean number of natalizumab infusions 34 (SD 11.4)) referred to a German University Hospital.

RESULTS:

Eight patients developed seizures during PML (53.3%). Six had grand mal, 3 simple partial motor and 2 psychomotor seizures at least once. Seven had series of seizures or status epilepticus, often refractory to antiepileptic treatment. Seizures occurred with a mean delay of 61 days (SD 41,5) after diagnosis of PML. Corresponding to seizure onset, gadolinium enhancement at MRI was detected in 5 patients, indicative for an immune reconstitution inflammatory syndrome (IRIS).

Six patients received PAT treatment with levetiracetam (1000 - 1750 mg per day) without any side effects. Patients with and without seizures and with and without PAT did not differ in sex, mean age at diagnosis of NAT-PML, mean number of natalizumab infusions, immunosuppressive pretreatment and in administration of mefloquine (2-tailed Fishers Exact Test & 2-tailed Mann-Whitney Exact Test p>=0.09). Patients who received PAT (n(total)=6; n(seizure)=1) had significantly fewer seizures than those who did not (n(total)=9; n(seizure)=7) (2-tailed Fishers Exact Test p=0,04).

CONCLUSIONS:

Seizures seem to be more common in NAT-PML than in other types of-PML. Seizures occurred most commonly 2 months after diagnosis of PML during IRIS. This may explain higher seizure frequency in NAT-PML. PAT decreased the incidence of seizures significantly.

Although data are limited we propose that NAT-PML patients may receive PAT before development of IRIS.

Larger datasets are needed.

Category - MS and Related Diseases: Clinical Science

Monday, March 18, 2013 2:00 PM

Session P01: Multiple Sclerosis: Treatment Safety
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PostPosted: Sun Oct 06, 2013 4:35 pm    Post subject: (ECTRIMS) Occurrence & management of PML & IRIS Reply with quote

Presented at the annual ECTRIMS conference in Copenhagen, October 2-5, 2013:

Quote:
Management of risk in MS therapy

Friday, October 04, 2013, 11:05 - 11:25

Occurrence and management of PML and IRIS

R. Gold, B. Kieseier (Bochum, Düsseldorf, DE)

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by the human polyoma JC virus [1]. It usually occurs in the setting of immunosuppression, including in patients with HIV, malignancies, transplant recipients, and individuals treated with immunotherapies. The pathogenic agent is named JC virus, after the initials of the index patient John Cunningham. A JC virus carrying a specific mutation affects oligodendrocytes and leads to cell lysis and consequently to demyelination predominantly of the human CNS white matter.

By now we have more than 370 multiple sclerosis (MS) patients suffering from natalizumab-associated PML. Over the last five years we have made substantial progress in both identifying risk factors for development of PML in MS patients, but also better handling the disease and reducing collateral damage occurring during immune reconstitution inflammatory syndrome (IRIS). Thus the outcome of natalizumab PML with around 80% survivors is much better than in the context of HIV-PML, and may even be better at specialized centers [2]. In the following we will summarize novel aspects of understanding PML and treating this devastating disease.

1. The risk factors: long-term exposure to natalizumab and latent JC virus infection
The majority of the population has been exposed to the JC virus - mostly before the age of 15, and about 60 to 80% of the adult humans exhibit a persistent antibody response against JCV, which seems to be the most reliable tool to detect latent infection. Unfortunately, approaches to detect relevant viral load via PCR in serum or urine turned out to be nonreliable in the general population [3]. A major breakthrough was made when Gorelik et al [4] established a two-step ELISA which allowed to detect a relevant JCV-load in 53% of MS patients, whereas 47% reacted negative; the available pre-PML sera from 17 infected MS patients were JCV-positive. These numbers were grossly confirmed in other geographic populations. Of note, the group of Chan [5] reported that the annual JCV-conversion during treatment with natalizumab may be as high as 5%, clearly above the levels in healthy controls. Thus, one should keep a watchful eye on longterm natalizumab recipients and control their JCV status every 6 months in anti-JCV-negative patients, as recommended by the EMA and FDA.

Testing for anti-JCV antibodies allows us, in conjunction with epidemiologic data collected by Biogen, to assess the risk for PML under natalizumab. For JCV negative patients this is virtually zero, and 1 or 2 borderline results of pre-PML sera were finally positive in the novel, second generation assay which is more sensitive. If patients are anti-JCV antibody positive and exposed for 24 months and longer, their risk has been calculated in a range around 1: 220 and this is pertinent over the following years - you can never say that someone who is JCV positive and received more than 5 years of natalizumab is out of the risk zone. The highest risk of PML occurs in JCV patients receiving immunosuppression before natalizumab, where the rate comes to about 1:90.

Recent evidence suggests that anti-JCV antibody levels may be useful in predicting the risk for developing PML in patients treated with natalizumab. In a recent study in a Swedish cohort five patients developing natalizumab PML revealed an increase of anti-JCV levels prior to the diagnosis suggesting that monitoring antibody levels may become a useful tool for predicting the PML risk in patients treated with natalizumab [6]. Biogen Idec is currently exploring PML risk estimates based on different anti-JCV antibody index thresholds in anti-JCV antibody positive patients with no prior immunosuppression. If confirmed in larger cohorts, such an antibody index may represent an additional tool in assessing the PML risk in MS patients treated with natalizumab.

2. Recent progress: predictive role of L-selectin expression on lymphocytes for PML
There is a clear need to improve the risk assessment on an individual basis. Along this line, the Wiendl group [7] studied PML patients from 10 European and US cohorts. Of 289 patients with MS, 224 had been treated with natalizumab (18-80 months). They also had access to samples from 16 natalizumab PML patients, eight of which had given blood before development of PML. Further controls included non-natalizumab PML cases. The percentage of L-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment or healthy controls (61.0%). A 9fold lower percentage was highly correlated with the risk of developing PML in the patient group with available pre-PML samples when compared with non-PML natalizumab-treated patients. Thus, the future will show whether this easy, FACS based assessment of the percentage of L-selectin-expressing CD4 T cells may provide an urgently needed biomarker for individual PML risk assessment.

3. Outbreak of PML and management of IRIS - novel aspects

Basically PML following long-term exposure to natalizumab exhibits similar clinical features [8] like other causes of PML: an early occurrence of cortical symptoms, seizures depending on the primary infection focus and a slowly progressive, relentless course. Since we always have the differential diagnosis of MS relapses in mind, we should consider that optic nerves are not [affected] by JCV which only causes retrochiasmatical lesions, and also spinal symptoms are not caused by JCV but rather reflect MS relapses.

The most critical point is - think of PML as differential diagnosis to MS relapses under long-term-natalizumab as early as possible! In contrast to other aetiologies we here have the chance to remove natalizumab within 3-5 sessions of immunoadsorption/plasma exchange and thus reconstitute the immune system and immunosurveillance of the brain within 3-4 weeks. Any delay in starting this sequence causes further viral spread, which is initially not visible on MRI since it only results in cellular infection, but later on the dues have to be paid during IRIS phase (see below).

Even more fatal is an ongoing series of natalizumab infusions because of misdiagnosing inadvertently MS relapses; some patients from Northern and Eastern Germany have been treated that way.

The German Paul Ehrlich institute has led a consortium of scientists for making PML diagnosis [9]. The state of the art is still PCR-based, quantitative JCV analysis in cerebrospinal fluid. Typically the lab or Dr. Eugene Major at NIH has the best experience, but also national polyoma virus reference labs may deliver a good standard. To our experience, we received some false-positive findings from non-academic labs and would clearly recommend to stay with the above referenced setting.

What to do if CSF analysis for JCV is negative? Always give clinical features highest priority, and never continue natalizumab before you have definitely excluded JCV infection! In patients with low viral load the CSF at lumbar level may already be cleared of virus, also PML lesions far away from the ventricles may be much less prone to have positive CSF findings. In all these cases, do another one or two taps and you may also consider then to involve the NIH laboratory as gold standard. Still there are JCV-negative CSF samples, where the final diagnosis can only be made via brain biopsy at experienced centers with high-level neuropathology.

The role of MRI is rather adjunctive at this level: you may see MS-atypical white matter lesions extending into the U-fibers, and usually no or only faint gadolinium uptake. We rather take this as [an] additional hint when deciding about brain biopsy, but we never rely on this for making the diagnosis. Also we try to avoid steroids during this early phase, since this can further support viral spread and as we know, also some MS relapse are steroid non-responsive.

After plasma exchange procedures you usually see a mild improvement for 2-3 weeks, and we would like to call this 'PML honeymoon' since the immune system has come back and started clearing high-viral load cells. But the more time goes by, there is full recovery of immune system and then [the] IRIS phase starts: the lymphocytes eliminate all infected oligodendrocytes and glial cells, even with low JCV copy number. Thus an increase of JCV copy levels occurs in CSF, to new lesions so far not visible appear on MRI. This usually goes along with marked clinical deterioration, diffuse Gd-enhancement and may finally afflict a whole brain hemisphere.
At that stage a basic decision should be made with the patient, or his testimony should be considered [about] how far intensive care unit medicine should go ahead. There may be necessity for artificlal ventilation for some weeks [10], and also tracheotomy and PEG tubes may be needed. If you really provide all the aids of modern medicine, the survival rate may go up to 100% [2]. Yet the final outcome is still very much dependent [on]whether the initial lesion is more in the frontal lobes or the thalamus/brainstem, thus introducing a bit of fortune at the individual level.

When IRIS starts and Gd+ lesions flare up, steroids clearly have a central role. We prefer pulse with 1000 mg methylprednisolone i.v. for 3 days, and if needed repeat again in the following weeks. The main purpose is to suppress bystander inflammation leading to collateral damage. Always keep in mind that this is a double-edged sword: if you perform too [much] suppression of the immune system, then viral spreading may still occur. Also be aware that most patients during IRIS have (secondary) generalized seizures. This is the only situation where we really add antiepileptic meds prophylactically, e.g. levetiracetam (Hoeppner, Gold in press).

4. Outlook

Still we have a lot of open questions to be handled in the future: why can some MS-PML patients not eliminate the JCV? Probably more information is needed in immunogenetics.

Which is the best follow-up treatment for MS after natalizumab PML? With the novel therapies out soon, we may have more options and experienced decision must be made since numbers are too small for randomized trials. Despite major achievements in understanding PML and assessing the risk in the context of natalizumab we still have a lot to do in the future.


[Reference list omitted.]
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