Risky business

While investors and analysts are investigating the risky business of pharmaceutical investments, patients, carepartners and their neurologists are also considering the risk of PML with the use of Biogen Idec's (BIIB) Tysabri (natalizumab).

As we have said in the past, the difficulty in accurately predicting the risk of PML, is that the numerator keeps changing (is it 13, 23 or ..?), while the denominator changes much more slowly.

There has been question about a "drug holiday," the problem is that we don't have any data to suggest that this would help (on the other hand, we don't know that it won't). Perhaps a drug holiday (coming off the medicine for a certain period of time) simply helps because the immune system reconstitutes and so there is less exposure time to the medication.

There may be an independent risk for activation of the JC virus (causing progressive multifocal leukoencephalopathy) each time it is given. This would mean that there is a risk month 1, 2, 3, 4 .... and that risk is no different in month 30 from month 13, except that there is a greater chance that PML will occur because there is a monthly (continuous) risk. If this is the case, a drug holiday, in itself, only reduces the PML risk because a person is on less of the Tysabri.

The real difficulty lies in the patient, carepartner and neurologist weighing the risks of treatment vs. the risk of the MS. Supposedly (and hopefully) a patient on Tysabri is on the medication because it is absolutely necessary for that individual, not simply because of a fear of needles (IV needles are a lot bigger than the intramuscular and subcutaneous needles used with the other disease modifying agents).

So what are the European Medicines Agency (EMEA) and the Food and Drug Administration (FDA) going to do?

If someone's Multiple Sclerosis is in need of a medication like Tysabri, then the risk of being off the medication may not outweigh the risk of being on it.

That is why everyone is an individual.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

High-lighting medical marijuana

State vs. Federal government.

Maybe it is fitting that there are 13 states with medical marijuana laws (13 colonies?).

The news this past week was that the Department of Justice decided that it should focus on bigger ticket items than prosecuting people following state laws concerning medical marijuana.

This debate is interesting, in that it may be dividing people along party lines, but these lines seem crossed (think state vs. federal control).

The glaring issue is, however, that as much as people are vocal about the potential benefits of marijuana/cannabis, if used with medical claims, it should have the same burden of scientific regulation that every other product you want to make a medically-related claim about.

Remember the FDA's warning letter to General Mills in May 5th, 2009, about Cheerios® their promotion of the cereal for conditions, which cause it to be a drug because the "product is intended for use in the prevention, mitigation and treatment of disease."

If this tasty Toasted Whole Grain Oats Cereal needs to follow these guidelines, why shouldn't those who make medicinal (may, not evidence-based) claims.

Consistency is key.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Extended release ... extended

Shocking? ... No.

Disappointing? ... Yes.

On October 14th 2009, the Peripheral and Central Nervous System Advisory Committee (panel) to the FDA's Acorda (ACOR), questioned Acorda about their planned REMS (Risk Evaluation and Mitigation Strategy) for Amaya (Fampridine-SR).

In response to this, Dr. Ron Cohen (President and CEO of Acorda Therapeutics), highlighted, once again, his professionalism and dedication to patient care, by amending the NDA (New Drug Application) submitted to the FDA. This prompted the FDA to extend the PDUFA (Prescription Drug User Fee Act) date from October 22nd, 2009 to January 22nd, 2010.

So what should we, the MS community, do about this?

Instead of wallowing in self pity, we should take this opportunity to create a 4-Aminopyridine (Fampridine-SR) community of advocates.

Think about what happened when patients demanded that the FDA allow Tysabri (natalizumab) come back to the market after the original three PML cases.

So, if you like the idea of extending functioning, improving walking and moving MS functional and symptomatic treatment forward, please email us at neurologique@gmail.com.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

What Amaya is not

A disease modifying agent.

Well, no one claims it is; it may improve functioning (and certainly improves symptoms), but it is not a disease modifying drug (DMD).

Why do I bring this up?

At www.neurologique.org, we have had a lot of queries lately, such as "Amaya vs. Copaxone?"

The FDA approved the medications to reduce relapses (there is nothing in the package insert that states "disease modifying drug") and so the concept "disease modifying drugs" was invented by the marketing divisions of pharmaceutical companies to describe what, is probably correct -- that the medications change the course of the disease.

One could argue, however, that simply reducing the relapses may not be enough, that a medication should also prevent disability.

What about improving disability?

Isn't that what Amaya does?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

To clarify, these are the medications approved for MS:

- Avonex (interferon beta-1a i.m.) .............. Biogen Idec

- Betaseron (interferon beta-1b s.c.) .............Bayer

- Copaxone (glatiramer acetate s.c.) .............Teva Neuroscience

- Extavia (interferon beta-1a s.c.) .............. ...Novartis

- Novantrone (mitoxantrone i.v.) ..................EMD Serono

- Rebif (interferon beta-1a s.c.) .....................EMD Serono

- Tysabri (natalizumab i.v.) ............................Biogen Idec and Elan

The Price Is Right!

No games.

Considering the pending (hopefully) approval of Acorda's (ACOR) Amaya/Fampridine-SR, let's explore the potential pricing.

Some have notice my comments on pricing:

http://www.ft.com/cms/s/2/b7b50454-af64-11de-ba1c-00144feabdc0,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html

I would like to clarify this:

1. Just because a drug is cheaper, does not make it better.

This is important from a safety point-of-view, and may be similar to the outcry by neurologists, nonprofits and patients regarding generic substitutions of epilepsy medication (antiepileptic drugs or AED). To sum this issue up, while generics are good because they are less expensive and are similar to the branded drug, there may be more variation when changing from one generic to another to another (as is done by retail pharmacies as their arrangements with the makers of generics change based on pricing deals).

For more on this, see the article from Neurology:

http://www.neurologique.org/Generic_Topiramate.html

So, the converse may be true: if you have a drug that could potentially cause seizures, if the dose was wrong (e.g. Amaya), then it may be dangerous if the blood levels of the medicine fluctuate depending on the batch of medication. This can be seen in, both generics and compounded medications.

This doesn't mean that compounding pharmacies are bad, they have served their purpose and have helped greatly, prior to Acorda taking a lead on getting this important medication FDA approved (hopefully this week).

If we ever see LDN (low dose naltrexone) take off, then we will have compounding pharmacies to thank for keeping the hopes alive (and ensuring that patients don't need to mix their own 50 mg naltrexone tablets in water and try to get the right amount).

2. Amaya's pricing question is not unique: compounding pharmacies often charge less for drugs than they cost when made by large companies (with stricter standards). An example of this was Rogaine. An example with a similar price struggle is transdermal (trans = across; dermal = skin) Testosterone. Compounding pharmacies may sell this at USD $85, while retail pharmacies charge USD $350 (Androgel or Testoderm) per month. This translates into a yearly cost of $1,020 at the compounding pharmacy vs. $4,200 at the retail pharmacy.

So, how do we summarize these two points:

1. Amaya will be safer than the compounded form.

2. Amaya's pricing issues are no different than other medications.

Here's to Amaya!

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

FDA gives clearance for Natalizumab (Tysabri) PML risk

PML risk is still under 1:1,000

The FDA stated that the range of PML risk is 0.4 to 1.3 per 1,000 patients in those who received at least 24 months of Tysabri (BIIB and ELN; Biogenic Idec and Elan).

The Food and Drug Administrations's comments the risk progressive multifocal leukoencephalopathy can be found here:

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107198.htm

They are summarized as:

"the overall rate of developing PML with Tysabri therapy in patients who have received at least one infusion remains below one per 1,000 patients. "

And: "the FDA is not requiring changes regarding PML to the Tysabri prescribing information or to" TOUCH.

So, Tysabri still gets the green light.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Infantilizing patients, stigmatizing language and pthe roblem with scientific proof

Open Letter:

Dear Barbara Ehrenreich,

In your recent book, entitled, Bright-sided: How the Relentless Promotion of Positive Thinking Has Undermined America, you point out how the teddy-bear movement in the pink world of the breast cancer movement, may infantilize people with breast cancer.

I want to thank you for highlighting how nonprofits may infantilize the very people they are supposed to serve.

As an MS (Multiple Sclerosis) doctor, I have watched young representative of nonprofits speak in a condescending manner to highly intelligent people, who just happen to have MS.

I hope that your fresh look at what has been bothering many of us, will be eye-opening (and cause soul-searching) for those who are attempting to serve others.

My only fear is that your insights don't encourage people to swing the other way and use stigmatizing language when referring to various diagnoses. A person is not diabetic, but a person with diabetes. Just as someone who has been in a car accident, is just that, a person who has been in a car accident.

Also, you commented, on NPR, that it has been scientifically proven that positive thinking does not help people recover faster. I would caution you, however, from making bold claims of scientific proof, as we know that half of what we know in medicine, will be reversed in 20 years.

The only problem is, which half?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

What's in a name

A lot.

As the FDA gets closer to its PDUFS (Prescription Drug User Fee Act) on October 22, 2009 for Acorda's (ACOR) Fampridine-SR, the name will also be changed to Amaya.

So, what does Amaya mean?

Amaya is Japanese and Arabic for night rain.

"A-" sometimes mean "a," "on" or "not".

"Maya" is Hindi for illusion (or, more positively, dream).

More importantly, perhaps, Maya is very similar to ma'ayan, which is Hebrew for spring (as in a spring of water).

Maybe, "a" "maya"n portends well for the MS community, as the FDA will (hopefully) grant approval in the "not" "spring," i.e. the fall.

October is still Fall, right?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

FDA Advisory Committee: ..... YES!

Thank you!

In a step forward for symptomatic treatment in MS, the FDA Advisory Committee today said "yes" to Acorda's (ACOR) NDA application.

This is a very good sign and I would be surprised if the FDA in its October 22nd meeting says "no." The only thing that may prevent this final decision, is the suggestion that Acorda should study even lower doses of the medication (as the lowest dose studied is the one that they are choosing, so we don't know what would happen with an even lower dose).

Let's hope the FDA says those studies can happen after the approval. I, for one, would be happy to conduct this type of post-marketing study.

I guess, everything is a little unusual nowadays.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

LIVE: FDA on Acorda's Fampridine-SR

The FDA's PNS and CNS Advisory Panel is in the process of taking hearings on Acorda's (ACOR) Fampridine-SR.

It seems that part of the risk of overdosing on Fampridine-SR is that patients feel good on it and may take too much on purpose. I get around this with the compounded version of 4-Aminopyridine by only giving it to patients I know wouldn't take additional doses, even if they felt better.

This patient attitude testing will be part of the REMS (Risk Evaluation and Mitigation Strategy), as will a specific specialty pharmacy; does this mean that primary care physicians will not be able to prescribe this drug?

How about regular neurologists?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Playing Awareness

Tebow is playing ... and winning.

Here is a useful comment from Facebook:

Nice interview Dr. Kantor. As a certified athletic trainer for three local high schools here in Clay county, we have started using preseason baseline concussion testing and a similar "return to play" protocol that you spoke of. Unfortunately it has taken such a big name sports star getting hurt to have people realize how dangerous a concussion can be. At least the word is getting out there, and parents may stop saying " He's ok, he just got his bell rung". Thank you for time and time and expertise in Sport Related Concussions and Head Injuries.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Tim Tebow: Concussion -- check out the story and video

Tim Tebow ... Superman, or not, highlights concussions.

Since the Channel 4 Morning Show (WJXT) we did yesterday, there have been many requests for the story link.

You can read the story here:

http://www.news4jax.com/sports/21253648/detail.html

And if you want to skip right to the video, visit:

http://www.news4jax.com/video/21250027/index.html

Enjoy the show ... and the game!

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Fampridine-SR's long trek to approval

Where are the patient's clamoring for Fampridine-SR?

We know that Acorda Therapeutics' (ACOR) Fampridine-SR works for MS patients by hy affecting the potassium channels (and hence the action potentials), so why is it taking so long to get approved by the FDA?

The FDA posted the following question for the October 14th, 2009 meeting of the

Peripheral and Central Nervous System Drugs Advisory Committee, and my responses are below them (bold).

Let's address the FDA comments each separately, my comments (which can be quoted are in red).

1) Has the sponsor demonstrated substantial evidence of effectiveness of fampridine as a treatment to improve walking in patients with MS?


This depends who you a the FDA itself said that they met their primary endpoints.The question is, are these significant clinically?

From using compounded 4-Aminopyridine extensively, there is no question that the answer is, a resounding yes.

2) If so, has the sponsor demonstrated that this effect is clinically meaningful, either in the group of fampridine-treated patients as a whole, or in a specific subset?

Have the makers of the beta interferons or gatiramer acetate done this either?

3) If so, should the sponsor be required to evaluate the effects of doses lower than 10 mg BID?

There is a strong possibility that the FDA will require this (ala the FTY720 studies).

4) If so, should this be required prior to approval?

In my opinion, no. This is because they have met their primary endpoint and not every drug has to do this. The FDA may take another track, though.

5) If substantial evidence of a clinically meaningful effect has been demonstrated, do you conclude that there are conditions under which fampridine SR could be considered safe in use for this indication?

Yes. It is unclear what this question is getting at, or is it simply repeating the question of approval?

6) If so, what are those conditions (e.g., specific enrollment criteria, specific monitoring, etc.)?

This attempt at limiting its use is, in my opinion, dangerous (and a slippery slope) as we do not do this with every drug. Does compazine (prochlorperaine), which lowers the seizure threshold, have to do this as well?

What does this mean for Sanofi-Aventis' development of Nerispirdine (affecting both the potassium and sodium channels but possibly without the seizure risk).

MS patients demanded Biogen Idec (BIIB) and Elan's (ELAN) Tysabri (natalizumab) be re-released by the FDA, despite the PML (progressive multifocal leukoencephalopathy), so where are they now?

What do we do in the meantime?

Well, there is always compounded 4-aminopyridine.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Autoimmunity, immunity, retroviruses and fatigue

NK (Natural Killer) cells are cytotoxic (cyto - cells; toxic - kill) lymphocytes (white blood cells); they help with rejecting tumor cells and viruses. Their mechanism is that the release granules with proteins (perforin and granzyme) inside that cause the cells they are attacking to die by programmed cell death (apoptosis).

In multiple sclerosis (MS), we usually talk about T-cells and, more recently, B-cells -- but NK cells are also differentiated from lymphoid progenitors.

NK-cells do not express T-cell antigen receptors (TCR) or Pan T marker CD3 or surface immunoglobulins (Ig) B cell receptor but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, and NK1.1/NK1.2 in certain strains of mice. Up to 80% of NK cells also express CD8.

Why is this important?

XMRV has been associated with chronic fatigue syndrome (CFS) by infecting NK cells, but XMRV is also found in prostate cancer cells, so maybe we are just learning more about a different retrovirus.

Still, this gives us pause.

Also, we are paused by NASA's NASA's Lunar Crater Observation and Sensing Satellite (LCROSS), planned and successful crsh into the moon to raise a plume of debris, which was collected by a probe, to search for evidence of ice on the "dark side" of the moon (the other side seems to be too fizzled out by the sun to have any water.

This has been seen as damage to our moon (and even "poking" out the face of the man in the moon). At first, I was also bothered by our fiddling (pun) with the moon, but then I remembered how much we do so with out own planet.

Food for thought.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

President Obama and Tim Tebow

The Heisman Trophy and Noble Prize.

Connected ... how?

The Norwegian Prize committee in Oslso, Norway, announced on October 9th, 2009 that the Noble Prize for Peace (Noble Peach Prize) has been awarded to President barack Obama.

This announcement comes and a surprise to many, including the Norwegian speaking staff. President Obama was awarded the Prize, normally reserved for those who have demonstrated an accomplishment central to the World's quest for peace, to Obama for his message of Hope.

This historic announcement follows a long line of history-making by the 44th President of the United States.

There was no surprise when Tim Tebow, (arguably) Florida's (most famed) quarterback won the 2007 Heisman trophy (sometimes misspelled, Heismann), but his recent September 26th concussion against Kentucky raises questions about his readiness (and medical learance) to play Number4, LSU.

It has been reported that this was his first concussion, but this is hard to believe as he has been active for so long and 85% of concussions go undiagnosed.

The real question is what grade concussion he had: he passed out and lost consciousness for brief seconds, making this a Grade 3 concussion (seconds), but he was seen to be vomiting while taken off the field, raising the unlikely possibility that this should be considered a more severe concussion. Other early concussion symptoms include, headache and dizziness (vertigo).

If this is considered a brief (seconds) Grade 3 concussion, then the guidelines recommend him not returning to ply until he has been asymptomatic (during rest and activity) for one week; if it is considered a more severe Grade 3 concussion (minutes), then that time period is extended to 2 weeks.

Having one concussion seems to put a person at greater risk for having another, probably because the brain becomes more hypersensitive to external damage. Repeated concussions over a lifetime portends possible puglistic dementia (dementia pugilistica) and Mohammad Ali's parkinsonism, prompting NFL players to sign-up for a registry to eventually donate their brains to scientific study at boston University (BU).

So, how would I treat the headache associated with concussions?

I wouldn't want to worsen cognitive disturbances by initiating headache preventive medications (especially for young people), therefore. I usually perform great occipital nerve blocks and trigger point injection to break the headache cycle ... with great success.

For more on headaches and their treatment, contact us at neurologique@gmail.com or (904)834-3007.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

New injection techniques

As we get read for the introduction of oral medications, pegylated interferons and more monoclonal antibodies, the interferon companies (Bayer, Biogen Idec, EMD Serono / Pfizer and Novartis) as well as Teva, are trying to develop new injection techniques (disposable needles, "EpiPen"-type injectors, new technologies ala RebiSmart and more infrequent dosing regimens, such as very other day Copaxone, which, by the way, needs to combat the same difficulties of confusing Betaseron/Extavia).

Despite this, the Lancet Neurology Reflection and Reaction by Pittock (online September 11, 2009) has a picture of someone drawing uo Betaseron with a needle, like in the past; where is the new autoinjector (BetaLite) system?

While we are looking back, Pittiock's 2007 Lancet editorial Interferon

beta in multiple sclerosis: how much BENEFIT? also had an (for the American audience, at least) upside down cervicall MRI.

I guess things aren't as they seem.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

CIS - To Treat or Not To Treat: Aye, there's the rub!

CIS conflict:

In thinking about Miller's Lancet's editorial on PreCISe (Treatment of clinically isolated syndrome: to be PreCISe) - online Oct 7, 2009, it is important to reference Pittock's August 4, 2007 Lancet editorial( Interferon beta in multiple sclerosis: how much BENEFIT?) and Pittock's Lancet Neurology's online September 11, 2009 2009 Reflection and Reaction on BENEFIT's disappointing 5-year disability data (Uncertain BENEFIT of early interferon beta-1b treatment).

So, is there consensus?

Apparently not.

Also, did anybody notice the upside down brain MRI in Miller's Lancet editorial?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Positive Energy

Positive Energy or Common Sense?

On the radio a psychologist spoke about she has changed her practice from standard psychological approaches to "Positive Energy."

She gave two examples:

1. When a patient tells her that they are having a side effect from a medication, instead of not believing the patient and saying, that is not in the PDR so it can't be true" (Physician Desk Reference).

I hope that all doctors believe their patients.

An example of why anytime a patients says they are having a side effect, I believe them is that when Copaxone (glatiramer acetate) first came out there were patients who complained about flushing, chest pain, palpitations, anxiety, shortness of breath (dyspnea), throat constriction, and hivs (urticaria), which we now recognize as the immediate postinjection reaction that occurs in 16% of patients (and along with lipoatrophy is the greatest side effect of GA).

As a friend of mine commented: "Drugs may work or they may not, but they cause side effects 100% of the time."

2. She said that she herself had been through tough psychological times, and she made this sound like it was the exception, rather than the rule.

That isn't true.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

MSF: Great patient question

I love the MSF (MS Foundation) and we work closely together.

Here is a useful question from their "Ask the Doctor forum," which I am active in (I wanted to share it with you all):

Question:

1. I heard something about the use of every other day Copaxone injections working as well as daily injections. Are there any studies on this?

2. Do you know of any studies/recommendations of MonaVie (acai berry) in MS? Any other "natural products/diets known to be effective

3 Lastly, Regarding Fampridine SR, soon to be approved by FDA, how frequently was seizure a side effect? Is it significantly better than when it is compounded by a pharmacy? If you get a seizure related to the med, how long till you could drive again?

Thanks so much for your time...

Answer:

Wow – these are great questions important to the entire MS community.

1. There is growing evidence that suggests that every other day Copaxone (glatiramer acetate) may be just as good as daily GA. See:
http://www.thisisms.com/downloads/Co..._Other_Day.pdf

This has not, however, been proven and bigger trials are planned.

It is important not to jump to changing your injection schedule (despite the clear temptations to – remember Odysseus and the Sirens) for several reasons:

a. Every other day GA may not be as good as daily GA – that is why we conduct large clinical trials.
b. Even if every other day GA is just as good as daily GA for most people, that doesn’t mean that it will be just as good for you.
c. You shouldn’t make this kind of decision alone, and should talk to your neurologist. Remember that your partnership with your neurologist is two-sided – just as you wouldn’t want her to make changes without discussing them with you first, you should afford her the same respect.

2. I am not aware of any clinical trial studying MonaVie in MS. Remember that in MS the immune system is not low, but rather selectively “boost”ed already (your immune system is boosted in that it attacks your white matter covering the nerves (myelin) and the nerves themselves.

Vitamins that seem helpful as add-ons include, Vitamin B12 and Vitamin D. We are planning a study of an Ayurvedic herb, Ashwagandha in the treatment of MS-related fatigue. I think that these complementary (not alternative) medications may be useful in giving your MS tretment an extra boost, but should not replace standard disease modifying agents (especially as they become stronger).

The Swank diet has been proposed as a good MS diet – see: http://en.wikipedia.org/wiki/Swank_diet

I do feel that all of these extra therapies can be useful nd can be a great way of avoiding additional pharmaceuticals for your symptoms but none of them can replace your standard disease modifying agents. See my blog:
http://www.healthcentral.com/multipl...-197780-5.html

Please remember that there may be downsides with these “natural” remedies:

a. They can be expensive (without much “return on investment”).
b. They may place you even more in the “sick role” but forcing you to pop handfuls of these pills (did you see the Montel William video on the Oprah show?).
c. They may be harmful – boosting your immune system in MS is not necessarily a good thing.


3. 4-Aminopyridine does appear to reduce the seizure threshold because it makes nerves work better by improving the conduction of electrical signals, and when you do that in the brain it can cause extra electrical activity and cause a seizure.

The question becomes whether there is going to be a boxed warning on the Fampridine-SR label that says it causes seizure – for more on this, see:

http://www.ft.com/cms/s/2/b7b50454-a...b5df10621.html


In the studies of Fampridine-SR, the chance of seizures was about 1.1%. However, “the seizure-related events over all extension studies with fampridine-SR 10 mg twice daily to date show an incidence of 0.41 per 100 patient-years, which is comparable to a previously reported expected incidence of first seizure in an MS population of 0.35 per 100 patient-years.”
What this means is that there may be no additional risk for seizures for a person with MS taking the drug vs. a person with MS not taking it. Remember that people simply have seizures, whether they have MS or not. There may be a higher chance of having a seizure if you have MS because of lesions in the cortical (grey matter) areas, where seizures come from.

Compounded 4-Aminopyridine does not have to follow the strict FDA guidelines on batch-to-batch similarity and purity, this means that theoretically the compounded medicines you get today may be slightly different from the ones you got last week (there is a similar problem with generic drugs). With that said, I do use the compounded version, but only with specific compounding pharmacies that I trust.

Different states have different driving laws restricting driving after a seizure, and in some states it makes a difference if you had it caused by something or if it just happened on its own. The thought process with that is that if you have an unprovoked seizure then you are probably at an increased risk of having another one, while if your seizure is brought on by something specific and that something is no longer there, then you should not have that same risk of seizures.

The question then becomes: if the Fampridine-SR did not cause the seizure, then the seizure is unprovoked and has to follow (sometimes) stricter driving laws.

Even in states without driving laws for people with seizures, I tell my patients:
“If a small child ran into the street, are you sure that you would be able to avoid them considering that you may have another seizure.” When its put that way (responsibility to others), people usually choose not to drive (usually it is a 6 months to a year of seizure freedom that is needed).


I hope that this has been helpful. For more on these and other topic, visit: www.neurologique.org.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Mental Health Awareness Week

Neurology, Psychiatry and Psychology:

Neurology and Psychiatry/Psychology are intimately ties together and as the mechanism of disease processes becomes better understood, these diagnoses often transition to the field of Neurology (depression is getting there), but usually neurological diagnoses involve the nerves and their coverings, while psychiatric diagnoses involve the synapses.

Neurological diagnoses are often stigmatized, even with something as simple as stigmatizing language in the media. Psychiatric diagnoses have an even ore difficult time -- think postpartum depression and Tom Cruise and Brooke Shields, although this was very helpful in raising awareness (especially with those effective television commercials). Just think about how people perceive bipolar disorder -- it is incorrectly seen as a psychotic disorder as opposed to depression, with one episode of mania.

This week is mental health awareness week and we'd like to invite this community into Neurologique's efforts and that of the Florida NeuroAlliance (FLNA).

Unfortunately, I heard someone speak on a radio show and they said:

First you get your brain healthy with psychiatrists starting medications, then you go to psychologists for counseling.

Huh?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Fairness in clinical trial design - helping those in need

The ethics of placebo-controlled trials.

Is the FDA justified in demanding placebo-controlled trials nowadays when there are other FDA approved medications available.

We are seeing that nowadays our trials with placebo arms have milder patients than in the past; this is probably because a more severe patient is not going to be enrolled in a placebo-controlled trial when there are other therapeutic options available to them.

This does not only make it difficult for us to compare current ”modern” clinical trials to older ones, it also only gives us data for how these medicines work in milder patients than in more severe patients.

This means that when you face a patient with more severe disease, it is harder to know how much these medicines will really help.

Placebo-controlled trials are skewed (and unfair?) in that they select for milder patients.

So, not only do we not have medications for primary and secondary MS, we know relatively little about how these medications work in more severe relapsing-remitting MS.

As doctors, we always look out for our patients.

So, we have to ask ourselves:

1. Is this fair?

2. How can we fix this inequality?

Studies like Genzyme’s Care-MS II trial of Campath (alemtuzumab) vs. placebo, in patients who had had a relapse despite having been on a disease modifying agent for t least 6 months, may help us in studying a sicker MS population.

Many of us focus on the ethics of exposing patients to placebo, but what about the patients discriminated against who cant enter the trial for fear of worsening on placebo?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Global trials and tribulations

Looking for answers: comparing notes

OR

How global trials work

Yes, it isn’t good statistics to compare between (or among) different clinical trials, but the temptation is there.

So, how do we reconcile the impressive TRANSFORMS data (Fingolimod did over 50% better than Avonex in terms of annualized relapse rate), while FREEDOMS showed an almost similar (a little more) reduction in annualized relapse rate for those receiving Fingolimod rather than placebo.

In other words, if Fingolimod beat Avonex by so much, why didn’t it beat placebo even more?

Also, why don’t we (so far) ee the cancer risk we saw in TRANSFORMS, in FREEDOMS.

People and countries.

FREEDOMS was ex-US, so maybe the melanoma detection wasn’t as good as in the global trial, TRANSFORMS or maybe you need two things to develop melanoma from Fingolimod:

1. An underlying risk factor (genetic or environmental) for melanoma

2. Exposure to Fingolimod.

Maybe the patients in TRANSFORMS are fundamentally different from those in FREEDOM. Before we celebrate the relative lack of cancer in FREEDOMS, we need to wait for FREEDOMS II to help us further understand this risk.

FREEDOMS was placebo-controlled, which means that patients enrolling in the trial were more likely to be milder than those entering TRANSFORMS, where there was an active comparator (Avonex). This means that the reason the placebo arm in FREEDOMS did so well is the same reason why the CLARITY placebo arm did well, because the patients weren’t that sick (otherwise they wouldn’t have been enrolled in a placebo-controlled trial. So, if the patients enrolled in FREEDOMS had been similar to those enrolled in AFFIRM (Tysabri compared to placebo), then we may have seen an even greater reduction in annualized relapse rate in those receiving Fingolimod vs. those receiving placebo.

If we assume that Fingolimod’s annualized relapse rate reduction is superior to Cladribine (TRANSFORMS vs. CLARITY ), then why didn’t Fingolimod blow away placebo even more than it did in FREEDOMS?

At a certain point, even with a relatively mild patient group (where even the placebo will have a low annualized relapse rate), the arm receiving active drug cannot get below a certain annualized relapse rate. Remember, patients in these trials have had a relapse in the last year (or two in the last two years), so it would be hard for any drug to reach an annualized relapse rate below a certain threshold,. So, for example, if Fingolimod is superior to Avonex and even more so to placebo, we might not see that huge a reduction because the annualized relapse rate (almost by definition) is constrained (and will never become much lower, in the absence of a “cure”).

So, Cladribine got to an annualized relapse rate of 0.14 – 0.15 with the mildest patient population (see the placebo arm); Fingolimod got to an annualized relapse rate of 0.16 – 0.18 with a slightly sicker patient population (than the CLARITY study), and when the population was a little more severe (TRANFORMS), Fingolimod’s annualized relapse rate was 0.16 – 0.20. Finally, in AFFIRM, Tysabri’s annualized relapse rate was 0.25 in the sickest of all these MS populations.

What would have happened in a Tysabri vs. Fingolimod vs. Cladribine trial?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

LIVE -- web MS TV

Immeditely after virtual secondlife.com MS Town Hall meeting -- come see LIVE web TV on MS: oral medicines, Fampridine-SR, research and more. No registration needed: www.neurologique.org or www.ustream.tv/neurologique

Neurologique Live web TV broadcasting

Check out www.neurologique.org About us --> Events