Tysabri Webcast

[HarryZ]

Observer,

As for SPMS or PPMS, I don't know the mechanism of disease but I think back to the 5-yr old girl with an aggressive form of MS.

Yes, that was quite a remarkable story with that little girl but I think what we had there was a unique kind of situation that was perhaps more of an aberration than the norm. What continues to amaze me is how someone that young ends up with a disease like MS!

All the CRABs and other inteventions had failed, yet Tysabri seemed to stop the MS cold in its tracks. Could/should this example provide any hope to SPMS or PPMS sufferers? Dunno.

I don't know. Although there has been the odd exception with PPMS/SPMS , almost every medication has failed miserably and these patients just continue on their slide. Most comments that I have heard so far about Tysabri for this kind of MS is that it won't do much for it.

But I am going to give you one example of a medication for SPMS that has worked relatively well for one patient...and that is my wife! In 1996, she had to quit her job in nursing because of SPMS. By 2000, the symptoms were numerous...horrible fatigue, tingling and burning in her feet, bad digestion problems and extremely sensitive to the heat. There was nothing any of the docs could offer her.

In June of 2000 she started to use Prokarin, the transdermal histamine diphosphate patch medication. The results were amazing and quick. Within a couple of days the fatigue was 80% reduced, the burning and tingling in the feet almost gone and the heat sensitivity greatly improved. The digestion problem took a few months to improve. As well, the cognitive problems she had as well virtually disappeared. She started to walk better as well. But then, in March of 2001 she took an awkward fall and broke her leg in 3 places!! After that she suffered from terrible spasms and to top it off, add in bilateral sciatica. Talk about a set back.

I've not mentioned Prokarin on this board very often but decided to with the talk of SPMS. It doesn't work for everyone...1/3 of the users get multiple symptom relief, 1/3 get one or two symptoms relieved and 1/3 have no change at all. Totally painless to use and virtually no side effects at all. Quite a story behind how the drug came to be used. If you want to read about how they think it works, go to www.edmsllc.com, click on "research" and then on either the "laymans" or "professional"
explanation.

Marg's health is still quite fragile but with the Prokarin she has been able to function, some days better than others. I hate to think of what she would be like without it.

Harry

[optimist]

Has anyone seen a transcript of the Q & A portion of the Tysabri webcast? The site said to check back on Monday, the 20th, but can' find anything yet.

[HarryZ]

Looks like nothing has been posted as yet and no explanation as to why not. I wonder what's happening.

While we wait for the Q and A session to get published I read a section of the opening comments by the panel and came across the section that referred to the safety of monoclonal antibodies, of which Tysabri is one. Please note that I am posting this information simply to try and understand what Julie is trying to get across here when it comes to this type of medication.

Julie Farace states when asked about the safety of these monoclonal antibody drugs.... "We've actually taken the opportunity, since daclizumab is on the market-although we use it off-label in relapsing-remitting MS-to use it in those instances where we very much need treatment for patient who is just failing all other options at this point. And before Tysabri was approved by the FDA, we looked at the option of using daclizumab or Zenapax in these patients. It's very interesting infusion in that its different from another drug, Rituxan. The characteristics of the side effects that go along with Rituxan are a little more - you need to be a little more careful with who you give Rituxan to. The Zenapax actually we've had very little instances of infusion reaction - a very well tolerated drug- and so we feel that it's another class, another drug that actually can be helpful in this disease."

Well, here are a few comments from the Physician's Desk Reference on these drugs..


WARNINGS
Fatal Infusion Reactions: Deaths within 24 hours of RITUXAN infusion have been reported. These fatal reactions followed an infusion reaction complex which included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation or cardiogenic shock. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. (See WARNINGS and ADVERSE REACTIONS .)
Patients who develop severe infusion reactions should have RITUXAN infusion discontinued and receive medical treatment.

WARNINGS: See Boxed WARNING .

ZENAPAX should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy.
While the incidence of lymphoproliferative disorders and opportunistic infections in the limited clinical trial experience was no higher in patients treated with ZENAPAX compared with placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing lymphoproliferative disorders and opportunistic infections and should be monitored accordingly.
Hypersensitivity
Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to ZENAPAX and following re-exposure.

There are many more warnings written for both these drugs and for each one, the FDA mandates the most severe warning (which is referred to as The Black Box) be posted.

Now I am NOT intending to say WHATSOEVER that Tysabri is dangerous (the trials have not indicated this at all) but Julie spoke of the safety issue with monoclonal antibodies by including the above two drugs in a very "matter of fact" manner. Reading what she said and how she said it gave me the impression that this class of drugs was relatively simple to use and that there was little danger with them . The literature, needless to say, states otherwise. Is there anything else we should know about monoclonal antibodies?

Harry

[better2gether]

These are some of the comments of the MS physicians surveyed concerning the impact of Tysabri On Existing Therapies

"Physician 1: I think Rebif will be most negatively impacted by Tysabri because the only advantage it has is that is more potent than Avonex, and I think Tysabri would be a better option. In addition, I’m not impressed with the tolerability of patients if switched to Rebif. I can’t get anybody to tolerate it.

Physician 2: Given Tysabri, I wouldn’t use Avonex and Copaxone over time. Although SENTINEL was positive, Tysabri was clearly the driving force, so there is no case for combination. I would also say that about 50% of patients on Copaxone will eventually be switched to Tysabri, as Copaxone doesn’t appear to do much. The same is probably true for Rebif due to side effects. I think 40% of my Betaseron patients would switch. Therefore, all therapies would be affected but I think Avonex and Copaxone would be affected the most.

Physician 3: I regard Avonex and Copaxone as less intensive therapies. So there will be more of those patients who go on to become breakthrough patients and they are candidates for Tysabri. With Rebif and Betaseron, there are fewer exacerbations but there is also a convenience issue with a patient on Rebif getting 3 shots a week. So patients might want to switch to Tysabri for convenience. The worry with the high dose interferons is also that they might cause liver and blood abnormalities.

Physician 4: I am stopping patients on mitoxantrone. I believe it has a very high risk benefit ratio and I’m going to put all my patients that are on mitoxantrone on Tysabri.

Physician 5: Betaseron has been the longest on the market and if I have people on active disease then I tend to go with Betaseron. Rebif has been too painful for my patients and I’ll try and avoid Rebif.

Physician 6: It's true Copaxone might have an antagonistic effect with Tysabri because of its mechanism of action but I believe we know little about the mechanism of action of any of these drugs. I have no problem giving Copaxone in combination with Tysabri and I will first give it to patients who are already on Copaxone. I might run the risk of decreasing efficacy of Copaxone but all these drugs work at the periphery as well as centrally and I’m just going to see how it goes.

Physician 7: Rebif has not been that effective and there have been some tolerability issues related to it.

Physician 8: It never made sense to combine Copaxone with anything else. Maybe it makes sense to give Copaxone first for about a year or so and get more of these cells across the blood brain barrier and then to give Tysabri. There is definitely a theoretical fear that Tysabri might eliminate the effect of Copaxone altogether although there are no safety concerns here.

Physician 9: Haven’t had a much of a situation to use Rebif. But I still think Tysabri would affect all existing therapies – including Rebif –although it might not affect Avonex as much because its been studied in combination.

Physician 10: Rebif looks better early on during treatment but it tends to slow down.

Physician 11: I hope that none of the existing products are negatively affected. There is an opportunity for all of them as there is a need for choices for patients."

[carolsue]

better2:
who did this survey of physicians? who are these physicians?

carolsue

[better2gether]

Carolsue,

It's S.G. Cowen.

You can see it after 'Post subject' above my message.

better2gether

[HarryZ]

Better,

Those comments by physicians on "dumping" the CRABs in favor of Tysabri don't surprise me at all. I'm sure that Biogen is counting on this reaction.

If you look at this a little deeper you have to wonder just how much faith the MS docs placed in the CRABs all these years. Along comes a drug that has been approved on only one year trial data, hasn't really been used yet by very many MS patients and the docs are already talking about "jumping ship" and changing to Tysabri. And these are the same docs that insisted that you start on a CRAB as soon as possible because they were the only approved drugs for the disease. Now all of a sudden they mention the bad side effects, lack of tolerability, limited effect, etc. etc.!! It's no wonder the MS patient is so confused.

Harry

[bebe]

Harry- you are so right. Reading this makes me sad. It just goes to show you that physicians dont agree AT ALL on these therapies. Everyone is confused...I dont know why, the data is very clear. But the drug companies have confused everyone in order to promote their therapy.

I would like to know who these physicians are. Are they from large MS centers who have extensive experience with the CRABS? The problem is- you get a community neurologist who treats maybe 50 MS patients, hence they are not as experienced, making these comments. Let's ask someone who is treating 1,000 of MS patients if these therapies are making a difference. You will hear an overwhelming- Yes. Lets also ask him if high dose interferon is hard to tolerate. Most say its not a problem b/c they aggressively managed side effects. They dont just send a patient out the door with the prescription.

Ok, so now on to Tysabri. I know Neurologists want to be able to offer their patients the next best thing. When it comes to MS, there is no cure, its frustrating to a physician. They want to offer them something, anything new. There is so much unknown about this drug. I dont see how physicians and patients can jump on it without more efficacy and safety data.

[HarryZ]

Bebe,

Let's ask someone who is treating 1,000 of MS patients if these therapies are making a difference. You will hear an overwhelming- Yes.

Even in this group of physicians there are conflicting opinions. Dr. P. Behan's Pathogenesis of MS says the CRAB drugs are simply not very effective at all. The Cochrane Group has come out recently and stated that Copaxone is a waste of time for MS patients. Even the chief neuro at the large MS Clinic here told my wife a few years ago that the CRAB drugs aren't doing what they originally thought they would do.

As Dr. Behan says, the last 50 years of MS research has more or less turned out abysmal results....no known cause and certainly no cure....and the MS patient is still waiting for something that will help them with this curse of a disease!

Harry

[better2gether]

Questions And Answers About Tysabri (Natalizumab)

Q. What is Tysabri (pronounced tie-SAB-bree)?

A. Tysabri (whose scientific name is natalizumab, pronounced: nat-tal-IZ-zue-mab) is a laboratory-produced monoclonal antibody. It was formerly called Antegren. It has been recently approved for marketing by the U.S. FDA for relapsing forms of MS, based on data from the first year of two, 2-year clinical trials. Tysabri is designed to hamper the movement of potentially damaging immune cells from the bloodstream, across the “blood-brain barrier,” and into the brain and spinal cord. The drug inhibits this movement by attaching to alpha 4-integrin, a protein on the surface of immune T cells that normally enables them to adhere to and pass through the blood-brain barrier. Because of this mode of action, Tysabri is called a selective adhesion molecule inhibitor (or “SAM”).

Q: How is Tysabri different from the other approved therapies?

A. Unlike other approved therapies for MS (Betaseron, Copaxone, Avonex, Rebif and Novantrone), Tysabri is an agent designed specifically to impede the movement of immune T cells into the blood-brain barrier. Although the interferon betas (Betaseron, Avonex, Rebif) also influence the movement of immune cells through the blood-brain barrier, they have many other influences on immune function in persons with MS.

Q: Who should take Tysabri?

A. Tysabri has been approved for persons with relapsing forms of multiple sclerosis. That includes anyone whose MS undergoes waxing and waning of symptoms. Relapsing forms of MS may include those with relapsing-remitting MS, progressive-relapsing MS, and those with secondary-progressive MS who experience relapses.

Q: What are the most commonly reported side effects of Tysabri?

A. Results available from the first year of clinical trials indicate that the most common side effects included headache, fatigue urinary tract infection, depression, lower respiratory tract infection, joint pain and abdominal discomfort. The overall incidence of infection was similar between those on Tysabri and those on placebo. Serious infections such as bacterial pneumonia and urinary tract infections occurred in 1.3 percent of placebo-treated patients and 2.1 percent of Tysabri-treated patients. Tysabri has been associated with hypersensitivity reactions, including serious systemic reactions, which occurred at an incidence of less than 1 percent of patients. Longer term safety information is not available.

Q: What did the clinical trials show about Tysabri’s effectiveness?

A. First-Year Results from AFFIRM Study: The AFFIRM study of Tysabri alone is a placebo-controlled study involving 942 participants worldwide. Participants were randomly assigned to receive either 300 mg IV infusion of Tysabri or inactive placebo every four weeks. Those on active therapy showed a statistically significant, 66% reduction in relapse rate. The annual rate of relapses in the Tysabri group was 0.25 versus 0.74 in the placebo group.

The secondary outcomes for the study were also significantly different for the treatment versus placebo groups. Sixty percent of those on Tysabri developed either no new MRI lesions or no newly enlarging lesions (patches of disease activity), compared to 22 percent of the placebo group. MRI scans taken after the first full year of treatment showed that 96 percent of actively treated participants had no gadolinium-enhancing lesions (lesions that show active inflammation) versus 68 percent of the placebo group. The proportion of participants who remained relapse-free was 76 percent of the treatment group versus 53 percent of the placebo group, which was also statistically significant.

First-Year Results from SENTINEL Study: The SENTINEL study of Tysabri added to Avonex, compared with a placebo plus Avonex, involves 1,171 participants worldwide. For this trial, individuals using Avonex who continued to experience disease activity were randomly assigned to add Tysabri or placebo to their standard Avonex therapy.

The participants who had Tysabri added to Avonex experienced a 54 percent reduction in the rate of clinical relapses compared to those on placebo and Avonex. The annual rate of relapses in the Tysabri plus Avonex group was 0.36, versus 0.78 in the placebo plus Avonex group. MRI scans taken after the first full year of treatment showed that 96 percent of the Tysabri plus Avonex group had no gadolinium-enhancing lesions versus 76 percent of the placebo plus Avonex group. The proportion of participants who remained relapse-free was 67 percent in the Tysabri plus Avonex group, versus 46 percent in the placebo plus Avonex group.

The secondary outcomes for this study were also significantly different for the treatment versus placebo groups. Sixty-seven percent of those in the treatment group developed no new or no newly enlarging MRI lesions, compared to 40 percent of the placebo plus Avonex group.

Because the companies submitted an application to the FDA about halfway through the two-year clinical trials, the one-year data are informative but incomplete; the complete set of results from these studies are not yet available.

Q: How is Tysabri taken?

A. Tysabri is given by infusion into a vein every 4 weeks. This can be done in a doctor’s office, clinic or hospital out-patient station.

Q: How long does an infusion take?

A. About one hour.

Q: Are infusions painful?

A. A person getting an intravenous infusion will probably feel a sharp pain or some discomfort when the needle penetrates the skin and vein, but then the discomfort should subside as the infusion proceeds. There may also be discomfort when the infusion needle is removed and the site may or may not feel sore for a day or so.

Q: How long can a person take Tysabri?

A. It is not known how long Tysabri needs to be taken, or if there are any longer-term limitations on its use. The drug was approved by the FDA based on only one year’s duration of treatment. Further, post-marketing monitoring of safety will be undertaken to detect any unforeseen adverse events that may occur in persons taking the drug for longer periods.

Q: How much does Tysabri cost?

A. The wholesale price of Tysabri has been announced to be $1,808 per vial or dose, which would be $23,504 per year if taken every four weeks. By comparison, the average annual wholesale price of some other MS disease-modifying drugs include: $16,608 (Avonex), $20,553 (Rebif), $16,026 (Copaxone), and $17,827 (Betaseron).

Q: Will this medication be covered by Medicare?

A. At this point, Medicare tends to cover medications that are provided in a physician’s office, which should include Tysabri when delivered under a physician’s care. Specific details about Medicare coverage for Tysabri, however, have not yet been determined.

Q: Will my health insurance cover the cost of Tysabri infusions?

A. Each health plan determines its own coverage. In the past, new MS medications have seen relatively rapid acceptance for prescription coverage costs when such are in place. Individuals may consult with their physicians and health plans for more information.

Q: Should I switch from the disease-modifying therapy I’m taking now?

A. There is no direct information that indicates whether individuals who are using existing disease-modifying therapies should switch to Tysabri. This question is something that can only be answered through discussions between an individual and his or her neurologist. There is currently no available information about the relative benefits or safety of Tysabri in comparison with any other currently available treatments for MS.

Q: Where can I call to get more information about Tysabri?

A. Biogen Idec and Elan have established a toll-free number to help answer questions: 1-800-456-2255; they have also established a Web site at: www.tysabri.com

You may also contact the National MS Society at 1-800-FIGHT MS and check our Website for further updates.

[HarryZ]

Better,

Thanks for that easy to read summary on Tysabri.

I have one question relating to the serious infection rate suffered by those in the trial. Perhaps someone may be able to answer this.

It was reported that 1.3% of the placebo group experienced a serious infection of some kind. Almost double that rate happened with the Tysabri group. Why would 1.3% of the placebo group end up with some kind of serious infection? Is that rate normal for MS patients who are not taking any kind of treatment outside of the trial atmosphere?

Harry

[flora68]

Harry, I was also puzzled when I first read about the rate of serious infections in the placebo group. I thought it seemed like a lot, too.

Why, I thought, would roughly 1.3% of untreated MS patients, presumably with typically strong immune systems, be, at any given moment, suffering from a serious infection?

Well, after pondering this for quite awhile (an especially uphill battle today , but oh well), and after re-reading the results, I think I may have figured it out. I hope.

It occurred to me, in a rare moment of clarity , that this statistic probably referred to serious infections occurring over the entire period of the study, which was one year, which is of course very different from 1.3% of pts having serious infections "at any given moment". (Of course, that "at any given moment" quotes only me and was my mistaken assumption only, not necessarily yours or anybody else's .)

Anyway, reflecting on the diagnoses I've coded in my job as a medical coder for a family doc, I'm pretty sure that a mere 1.3% annual serious infection rate among our patients would be a tremendous improvement! (But then we have a lot of geriatric patients, most with multiple co-morbidities, and more Mexican-American patients than any other demographic group, which means lots of high cholesterol, which unfortunately means lots of diabetes and heart disease.)

But I'm guessing that a 1.3% rate of patients suffering serious infections at some point during a year might be reasonably expected among people with stronger-than-usual immune systems, such as many untreated MS patients.

Does that sound right to you?

[HarryZ]

Flora,

Does that sound right to you?

I assumed that the 1.3% serious infection rate was the overall rate for the entire placebo group for the one year period that was measured. But that number doesn't mean much if we don't know what the average rate of infection normally is for MS patients who aren't taking anything for their MS. The only stat we have to compare this with is that 2.1% of the Tysabri group had a serious infection. But what does this mean? Do Tysabri users expect to have almost double the serious infections than untreated MS patients? How about those on the CRAB drugs...what is their serious infection rate while on those medications?

I guess what I am trying to learn here is what the normal level of serious infections are for untreated MS patients, do they have more than the general population and has anyone ever looked into this situation before?

Back to your original question....I'm not sure what sounds right here!!

Maybe if Finn is lurking on the sidelines and reads this thread, he may be able to shed some light on this.

Harry

[finn]

Sorry, time to leave the board.

-finn

[HarryZ]

Finn,

Got a reply back from a MS medical person to whom I asked about the infections. She told me that she had heard a number of patients in the Tysabri trial (both placebo and drug users) ended up receiving steroid treatment due to exacerbations. Steroids suppress the immune system a lot and it wasn't surprising that many of them ended up with serious infections.

Harry