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I'm halfway between the first and second doses of Tysabri. When should I expect the neurologist have me tested for antibodies? 3, 6, 9 months, or longer? Would it be the same Athena Diagnostics back east that did my Avonex antibody testing? Or are there multiple labs that can do it?

My understanding is that there currently will not be testing for antibodies. If for some reason, you or the neurologist feels that there is a decline in status or less of an improvement than before, a repeat MRI would be ordered. I read somewhere that the company is working on the lab test for antibodies but is not released yet. I will see if I can find it.

Here it is:
A New Approach for MS
Thomas Morrow, MD

Since the mid-1990s, there has been revolutionary advancement in the understanding of the pathophysiology and treatment of multiple sclerosis. On November 23, the FDA issued an approval letter to Biogen Idec for natalizumab, a totally new approach to the treatment of MS. There are now three immunomodulation classifications available for the routine treatment of MS, including the three interferons, glatiramer acetate, and now a monoclonal antibody.

All of the classes have fundamentally different mechanisms of action. The interferons basically work by shoring up the blood brain barrier, preventing the migration of activated T cells into the central nervous system. Glatiramer acetate works by confusing the immune system into not attacking the CNS and activating protector T cells to actually decrease the inflammatory response within the CNS.

This new product, natalizumab, acts differently.

Managed care implications
It has a WAC price of $1,808 for a 28-day dose. The daily WAC price is nearly $65, compared to approximately $39 for Avenox, Betaseron, and copaxone, and $48 for Rebif when you take into account the 12 versus 13 dispensing units per year.

Natalizumab is also associated with considerable administrative costs, as it is expected to be administered primarily in physician offices and outpatient infusion sites. With Johns Hopkins University, Biogen has been providing educational programs (as is usual with physician-administered drugs) to neurology offices on the intricacies of office-based infusion, including benefit verification, prior authorization procedures, payer coverage policies, and appeal processes. There is instruction on coding and on setting up an infusion suite, and there is a special section devoted to revenue collection and opportunities for the practice. There is no specific HCPCS code for natalizumab, so the nonspecific codes J3490 "Unclassified Drug" or J3590 "Unclassified Biologic" are recommended.

We now have a new development and, in fact, the first entrant from a whole new class of medications available for the prevention of relapses for MS. But managing the patient who is living with MS is still difficult.

If neutralizing antibodies are present, the efficacy of natalizumab will be minimized. There is no test for the antibodies expected in the near future.
There is also the cost associated with natalizumab treatment, especially when administrative costs are considered.

Also, the safety problems of other monoclonal antibodies are well known. Natalizumab has a slight increase in infections and no current evidence of malignancies, but the worldwide experience is limited to a minuscule percentage of the population with MS. In addition, the long term efficacy is unproven in a population that now has open label trial results available for as long as nine years. Finally, there is the real possibility that providers will request combined therapy.

Management possibilities
What can managed care do? There are a number of management possibilities available for this new entrant. The choices are to:

Develop a stepped care approach with one of the interferons and glatiramer acetate as preferred,
Set up a prior-authorization system to validate lack of efficacy with standard therapeutic options before approving this new, more expensive, therapy,
Contract with a specialty pharmacy company (SPC) to avoid giving physicians an incentive to capitalize on the revenue stream,
Implement edits to an AWP discounted reimbursement, similar to what you would pay an SPC,
Screen data sources for dual therapy and challenge them as off label,
Establish a tracking system for relapses and subsequent progression of disability, the true endpoint of this devastating disease,
Contract for or develop a disease management process to maximize the outcome of patients with MS, focusing on preventing the progression of disability and on preventing or managing the comorbid conditions to avoid unnecessary hospitalizations for issues such as uro-sepsis, and
Demand head-to-head trials with existing therapies.
Tysabri's mechanism of action
Natalizumab is being marketed under the name of Tysabri. In early news releases, the company had proposed the name of Antegren, but changed the name before launch.

This compound is the first of several antibodies in the pipeline targeting different steps in the immune dysfunction that leads to the clinical condition we call MS.

The exact mechanism of action by which natalizumab exerts its effects in multiple sclerosis is not fully defined. MS is believed to develop when activated inflammatory cells, including T cells, cross the blood brain barrier. No one is sure how the inflammatory cells are activated, but the result is the presence of highly active inflammatory cells within the CNS causing destruction of the "insulating" myelin sheath around nerves. Once damaged, the nerves cease functioning normally and the neurologic effects become the symptoms of MS.

Before the inflammatory cells can cross into the CNS, they must bind to the lining of the blood vessels, the endothelium. Natalizumab is thought to work by preventing this binding and hence stopping the migration of the damaging cells.

Structurally, natalizumab is a recombinant humanized IgG4κ monoclonal antibody produced in murine myeloma cells. It binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes (except neutrophils) and inhibits the α4-mediated adhesion of leukocytes to their corresponding receptor. These α4 integrins are a family of integrins that include vascular adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MadCAM-1), present on the vascular cells of the gastrointestinal tract.

This binding basically disrupts the attachment of leukocytes to the blood vessels and prevents the migration of these activated leukocytes into the inflamed area; in the case of MS this is the central nervous system. Simply put, if the T cells establish a foothold on the endothelium, leukocytes cannot migrate through. Natalizumab prevents the foothold from occurring.

Infusion
The new treatment consists of a dose of 300 mg of natalizumab mixed with 100 mL of 0.9 percent sodium chloride injection, USP, administered during a one-hour infusion every 28 days. As with all proteins, mixing should be done gently to prevent damage to the large protein molecule. The mixed solution must be administered within eight hours. The product has a labeled shelf life of 15 months when unmixed and stored.

There are no dose adjustments for weight. Natalizumab is classified as pregnancy category C and has not been studied in nursing mothers. There were insufficient numbers of patients over 65 to make a recommendation, and the drug has not been studied in patients under age 18.

The most frequently reported serious adverse reactions with natalizumab were infections. According to the package insert the worldwide experience with natalizumab in both controlled and uncontrolled studies is limited to 1,617 total patients with a medium exposure of 20 months.

As is true of virtually all biologics, there are no head-to-head studies against the standard therapies. No meta-analysis published, but from this writer's uneducated observation, it appears that the actual relapse rate reduction is about the same as has been seen with the more proven therapies. Obviously there are no long term efficacy or safety data available.

Neutralizing antibodies
One very bothersome finding is the development of neutralizing antibodies that were, according to the prescribing information, detected in approximately 10 percent of patients receiving natalizumab. This became persistent in 6 percent of patients receiving the medication, so much so that it led to a "substantial decrease in the effectiveness."

In fact, the annualized relapse rate of persistently antibody-positive patients was similar to the annualized relapse rate in patients who received placebo. The assay used during the study was unable to detect low to moderate levels of antibody to natalizumab. The effects of low to moderate levels of antibody are unknown.

Accelerated approval
There is no commercially available neutralizing antibody test available, and the PI does not require its use in clinical practice. This issue appears to be very important to the FDA, as there were numerous requirements in the approval letter, including the development of a screening immunogenicity assay that will detect anti-natalizumab specific antibodies. The requirement is for the developments in the screening assay to be reported to the FDA by March 31, 2007.
This product was approved under the "accelerated approval of biological products" regulations 21 CFR 601.40-46, which allow the use of surrogate endpoints or an effect on a clinical endpoint other than survival or irreversible morbidity as the basis of approval. Other approved therapies have demonstrated improvement in the delay of disability as measured by the Expanded Disability Status Scale (EDSS).

Because of this, the FDA is requiring Biogen to perform adequate and well-controlled studies to verify and describe the clinical benefit attributable to this product. In particular, the FDA is requiring that Biogen verify that the clinical benefit of reduction in exacerbations is sustained with continued administration.

These studies are due September 2005. The FDA is also requiring that Biogen perform a study of the pharmacokinetics of chronically dosed natalizumab in the presence of glatiramer acetate — a portent of possible combination therapy.

This is the first generation of this class of drug. Time and experience with this antibody will demonstrate whether this class is as safe as the existing immunomodulators or if it is worth the premium pricing. That will be the topic of future essays on Tomorrow's Medicine.

Hi -

Thought I'd pass along the response I received from my neuro when I asked about testing. (I've had two infusions to date.) He said that not only is there not a commercial test available, but that he wouldn't test me anyway because there is nothing else he can offer me. (The interferons send my liver values sky high and the Copaxone injections bruised me too much.) I'm sure my insurance company wouldn't be thrilled to hear that. It seems like a lot will play out over the next couple of years: the development of a test, my personal experiences with/out relapses, alternative treatments.

I am curious to hear what other neuros have said regarding testing if anyone out there has had a similar conversation.

Thanks,
Arcee

The article that I posted actually prompted my questioning about the test. I did not as yet talk to my neuro, but I did speak with the case worker/representative from Biogen and a pharmaceutical manager who both concurred that the testing at this point is not available. If I understood correctly, when it is available, it would be ordered by the neurologist only if there is an issue with the drug...what may appear to be a decrease in its effectiveness. (more symptoms, more lesions on MRI). That would prompt looking into the possibility of the antibodies against tysabri.

When the test becomes available it will be a useful tool. My question is...how did they test the study participants and why can't the same be made available to us?

1) Since they tested for nAbs in the trial - it's obvious there is a technical way to test for it.
2) They stated specifically that nAbs make the drug ineffective - one would like to move to a different drug if that's the case – for newly diagnosed patients those are options.
3) I'm not sure if it's in Biogen-Idec's interest to release it - on the one hand it will take some patients of the drug, on the other hand - those that will take it will enjoy better efficacy.
4) If there is demand, some other company can make that test kit.
5) That is, if they don't need the trademarked drug a s a componant of the kit.
6) I’m not sure it’s a good idea to take it if nAbs are present even if other options are not available – why risk possible side effects? Is there any residual efficacy in those patients?

Guy

"Since they tested for nAbs in the trial - it's obvious there is a technical way to test for it......"

from Dr. Guy


You're right, Dr. Guy. There obviously was a test for NAb's to Tysabri used in the trials.

However...(and this would tick me off a bit if I were taking Tysabri) ...your doctor can't get the test done yet. It's "not commercially available", and probably won't be anytime in the near future.

The FDA gave Biogen until March 31, 2007 to present them with "a screening immunogenicity assay that will detect anti-natalizumab specific antibodies".

I hate to sound cynical, but somehow I doubt they'll be in a hurry to rush that test to the market before the deadline, but who knows? Most patients won't need it anyway, according to the prescribing info, therefore Tysabri NAb testing isn't a regular part of the Tysabri protocol at all, unless the drug seems to stop working.

But for those who do need or want to know their "anti-Tysabri titre", I guess just be patient.

BTW, this was all contained in the "Acelerated Approval" section of the article that MichelleMM pasted from "Managed Care Magazine".

Here's the address of that article, if you want it for some reason: http://www.managedcaremag.com/archives/ ... otech.html

Actually, there was another statement in that article that I wondered about more.

"As is true of virtually all biologics, there are no head-to-head studies against the standard therapies. No meta-analysis published, but from this writer's uneducated observation, it appears that the actual relapse rate reduction is about the same as has been seen with the more proven therapies. Obviously there are no long term efficacy or safety data available."

The author of that article, by the way, is "Thomas Morrow, MD, president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level."

This is certainly interesting about not testing for antibodies at the moment.

The one year data showed that 9% of the Tysabri users developed NABs with 6% having to stop the treatment for good because of this. I believe that they stated the NABs would show up within the first 6 months....or was it 3 months? Regardless, they must have measured these NABs during the trials so there must be something available to do the testing.

Harry

Information from the clinical study:

Patients were tested for antibodies every 12 weeks. The assays used in these studies were unable to detect low to moderate levels of antibodies to natalizumab. Antibodies were detected in apporximately 10% of multiple sclerosis patients receiving Tysabri at least once during treatment with peristent antibody-positivity in 6% of patients. Approximately 90% of patients who became persistently antibody-positive by this assay had developed detectable antibodies by 12 weeks.

Interesting that those of us that started Tysabri already will have been on it for over 2 years prior to the test becoming available.

Michelle,

Interesting that those of us that started Tysabri already will have been on it for over 2 years prior to the test becoming available.

This certainly is confusing!! You state that you've been on the drug for over 2 years but haven't had a NAB test. Yet, during the trials, they came up with these NAB numbers. So how did they do that if there wasn't a test available at the time? With 10% of the patients developing NABs, there had to be something being done?

Anyone have an explanation for this?

Harry

HarryZ wrote:Michelle,

Interesting that those of us that started Tysabri already will have been on it for over 2 years prior to the test becoming available.

This certainly is confusing!! You state that you've been on the drug for over 2 years but haven't had a NAB test. Yet, during the trials, they came up with these NAB numbers. So how did they do that if there wasn't a test available at the time? With 10% of the patients developing NABs, there had to be something being done?

Anyone have an explanation for this?

Harry

Hi Harry

I believe I can help, if you'll forgive my butting in. (Michelle is great at speaking for herself, but she doesn't seem to be on the board at the moment.

I'm pretty sure that Michelle's an infusion nurse who only started on Tysabri herself very recently; I know I remember her posting after her first or second infusion.

A careful reading of her recent post will show that she didn't really say she'd already been on Tysabri for 2 years; she said that she will have been on Tysabri for up to 2 years before the test is (commercially) available.

Hope that helps.

HarryZ,
To clarify, I meant that since the test is not required to be available until March of 2007 and I started Tysabri in January of this year, it may be 2 years until the test for antibodies is available to me.

That's correct Flora ! Except that I'm not an infusion nurse, I'm a surgical nurse. Thanks for helping me clarify.

MichelleMM wrote:That's correct Flora ! Except that I'm not an infusion nurse, I'm a surgical nurse. Thanks for helping me clarify.

Oops! Sorry Michelle .

No telling where I got the impression that you were an infusion nurse. I guess I sorta merged you with another poster.

Anyway, that's what I get for trying to 'multi-task'. While posting I'm also playing a gentle game of indoor frisbee with my dog, as well as paying a certain amount of attention to a favorite movie playing on the video, "The Thin Man". Lucky I didn't refer to you as "Nora"!

Michelle,

I posted an earlier message to Flora but for some reason it didn't go through! I told her she could "butt in" any time she wanted

I find this lack of NAB testing strange to say the least. Trial data shows that 10% of the Tysabri patients ended up with NABs and that 6% of the patients had to stop using the drug because the NABs would not return to normal. So they had to have some kind of test to do this.

The data also showed that the NABs presented themselves rather quickly (within a few months) and that's when the patients would be watched most closely. Now we are being told that there is no commercial test available yet! So how are these patients going to find out if they are in that 6% group?

Harry