Countdown

22 ... 21 ... 20 ... 19 ... 18 .......

It's the final countdown, but not just for New Year's 2010; we have 22 days to go until the PDUFA (Prescription Drug User Fee Act) for Acorda's (ACOR) Fampridine-SR (01/22/10).

2010 will be an exciting year for MS patients, families, loved ones and neurologists. In January, we should see the FDA approve the NDA (New Drug Application) for Fampridine-SR. Sometime in January, we expect Novartis (NVS) to file Fingolimod (FTY720) with the EMEA (European Medicines Agency) and the U.S. FDA (Food and Drug Administration). Although many of us expected the filing of Fingolimod's NDA to be in December 2009, it may still precede Merck KGaA and EMD Serono's oral Cladribine (Mylinax or Movectro) refiling after the disappointing Refusal to File (RTF) in November 2009.

In the spirit of advancement, and especially advancement of knowledge and education, I would like to take this opportunity to discuss various scenarios ('cases') that will face neurologists and patients with MS regarding the imminent approval of Fampridine-SR.

Although Compounded 4-Aminopyridine has some similarities to Sustained (Extended) Release Fampridine, it should be clear by now that these are, in many ways, different drugs and there is little justification to starting someone de novo on Compounded 4-Aminopyridine once Fampridine-SR is approved.

SCENARIOS:

Scenario #1

Mr. A is an MS patient with walking difficulties who has never been on Compounded 4-Aminopyridine or Fampridine-SR to improve their walking (or other symptoms helped by blocking the potassium channels and extending the electrical signals in the nerves; these other symptoms -- not endorsed by Acorda -- include, spasticity, pain, 'MS hug,' trigeminal neuralgia, Lhermitte's phenomenon, sensory symptoms, cognition, arm mobility, fatigue etc.).

Since Mr. A has never been on Compounded 4-Aminopyridine, it would make no sense to initiate it once Fampridine-SR is approved. The reasons for this include: safety, efficacy and tolerability.

Thus far it seems that Fampridine-SR 10 mg -- one pill twice a day, does not increase the risk for seizures. We know, however, that the mechanism of action whereby potassium channels are blocked, could theoretically lead to a lower threshold (as seen in higher doses). Since Compounded 4-Aminopyridine is made in a non-standardized fashion with variations from batch to batch in the same pharmacy and from pharmacy to pharmacy, patients may be receiving variable quantities of the actual medicine.

[The epilepsy community faces similar threats with generic anti-seizure medications, even though they are made in internally standardized factories; the whole issue is that there is variability among the different versions of the medication. Advocacy efforts have led to insurance companies recognizing the dangers to patients, as noted in a letter -- http://sparklightadvocacy.files.wordpress.com/2009/12/wellmarkongenerics.pdf ]

Compounded 4-Aminopyridine is not sustained release at here is wearing off of its effects.

The largest tolerability issue with Compounded 4-Aminopyridine (besides the risk of seizures) is gastrointestinal upset. Since Fampridine-SR is coated (allowing the sustained release), there is less tolerability issues.

Scenario #2

Mrs. B was on Compounded 4-Aminopyridine 2 years ago for 3 months, but had no noticeable change in her functioning or symptoms and therefore stopped the medication. Once Fampridine-SR is on the market, it would make sense to try it in this patient with walking difficulties.

Mrs. B may now respond to the Fampridine-SR because it is a better drug than the compounded version, in addition to her having accumulated more difficulty walking, and the effects of the potassium channel blockade are now more apparent.

Scenario #3

Ms. C tried Compounded 4-Aminopyridine 3 years ago, but had stomach pains or other tolerability issues with the medication. As noted above, Fampridine-SR has a better tolerability profile than Compounded 4-Aminopyridine and so Ms. C may have the beneficial effects of the potassium channel blockade without the unpredictable tolerability issues of the compounded medication.

Scenario #4

Mr. D tried Compounded 4-Aminopyridine 10 mg twice a day, 3 months ago and had a seizure, but on further clarification, there was a compounding error and the pharmacy prepared 40 mg twice a day. Mr. D wants to go back on the medication because he felt better while on it, until the seizure occurred.

This is a difficult scenario, since the seizure was because of an overdose of the compounded medication, and we know that even Fampridine-SR reduces the threshold seizure at higher doses; one could argue that Fampridine-SR should not be withheld from him because of a past compounding error. On the other hand, he may be at risk for future seizures. Like in all situations, a long discussion between the patient and neurologist is important. In addition, the family becomes crucial here because having another seizure has many implications for driving and working.

A middle of the road approach may be to wait until Mr. D is seizure free for a longer period (6 months? 12 months? 24 months?) prior to initiating Fampridine-SR. Other seizure risk fators need to be assessed (including the location of the MS plaques) and individual states have variable driving laws.

Scenario #5

Ms. E was on Compounded 4-Aminopyridine 10 mg (1 pill twice a day) for 2 years, but 3 years ago she had a seizure and stopped the medication (despite it helping her walking). On careful examination of the pharmacy records, it looks like there was no compounding error. This is an even more difficult scenario since it is possible that Ms. E may have a lower seizure threshold with Fampridine-SR, as well. Granted, 10 mg of Compounded 4-Aminopyridine is not equivalent to 10 mg of Fampridine-SR, but most patients do not have seizures at that dose of Compounded 4-Aminopyridine.

Since this scenario is so controversial, and there may be extenuating circumstances pushing us in one direction or another, I will not comment on it here (although some of my patients face this difficult situation and each one is going through individualized counseling). This scenario highlights the importance of a strong, reciprocal relationship between the neurologist and patient so that the nuances of care can be explored, discussed and agreed upon.

Scenario #6

Mrs. F has been on Compounded 4-minopyridine for the past 4 years, with what she calls an excellent response. Granted, she still has some difficulties with walking, but she is much better than she was prior to initiating the medication and she "wouldn't give it up for the world." This is a common question I receive; switching to Fampridine-SR makes sense for several reasons:

1. Mrs. F may have an even better response to Fampridine-SR, both in terms of magnitude and duration throughout the day.

2. Mrs. F may not be as functional as she could be. She knows that when she skips a few doses of Compounded 4-Aminopyridine she feels worse (and this tells her it is helping), she doesn't know if she respond even better to Fampridine-SR.

3. Although Mrs. F knows that her walking improves with Compounded 4-Aminopyridine, other symptoms may not be helped. Theoretically Fampridine-SR may help with these other symptoms, as well (longer acting, less variability etc.).

4. As we understand it, there is less of a risk for seizures with Fampridine-SR than Compounded 4-Aminopyridine.

5. Mrs. F may not realize that she is having tolerability issues from the compounded medication.

We all recognize that 2009 has been a confusing year (including the question of CCSVI) and I wanted to clarify some things as we look towards 2010.

Happy New Year and let's keep the ball rolling!

- Dr. Daniel Kantor, MD BSE

Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Relativity

We have discussed CCSVI and the Liberation procedure a lot (also see the web TV video of the recent MSF program, where there is a CCSVI discussion), but we need to remember the risks and benefits of immunomodulatory therapy (perhaps they will complement each other).

At the latest report (as of December 1, 2009), there are 28 "cases" of PML (progressive multifocal leukoencephalopathy) in post-marketing Tysabri (natalizumab) use. There have been, unfortunately, 7 deaths.

This makes the risk of PML as follows:

Overall (post-marketing): 0.43 per 1,000
=> 12 months: 0.76 per 1,000
=>18 months: 0.86 per 1,000
=> 24 months: 1.28 per 1,000
=> 30 months: 1.05 per 1,000
=> 36 months: 0.63 per 1,000


The utilization numbers (as of October -- so not the same time period) are:

Overall: 60,700
=> 12 months: 43,400
=>18 months: 23,000
=> 24 months: 13,400
=> 30 months: 6,400
=> 36 months: 3,00


So, what does this all mean?


We will have to wait and find out.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

On the other hand ...

Another false promise?

There has been a lot of excitement over CCSVI (Chronic Cerebrospinal Venous Insufficiency), because of the hope that we needed a paradigm shift in the understanding of MS.

The line of thinking was that thinned veins draining blood from the central nervous system (CNS), causes a back-up of blood and iron (one of its components) gets deposited in brain and spinal cord tissue. Instead of MS being a primarily autoimmune disease, the thinking was that perhaps MS is structural (based on the venous thinning) and that this anatomic anomaly causes a back-up of iron, which in turn provokes an immune response (trying to "clean up" the iron).

This notion is attractive because everyone with any lifetime diagnosis, wants to know why it is occurring to them, and wants to find a novel way of thinking about it -- so that an actual cure can be found.

It is easier to understand a vein problem than to grasp the notion of autoimmunity. In fact, autoimmunity raises many philosophical questions about self and non-self and what separates us from the other.

Unfortunately (or fortunately), the CCSVI hypothesis needs to be tested just as any other (and there have been many) new theory is tested -- through rigorous scientific and clinical studies and trials.

For everyone reading, please understand that neurologists want to help their patients and we are not wed to the idea that MS is primarily autoimmune, in fact many of us are leaning towards it being a neuro-degenrative or astrocytic mediated disease.

As neurologists, we appreciate budding sites, such as Liberating CCSVIcuresMS.com, Understanding CCSVIforMS.com and CCSVIliberation.com -- but we also need to act responsibly in order to protect the health of our patients. With that in mind, I recently attended a meeting of MS neurologists, where we had frank discussions about the data surrounding CCSVI.

The great hope of CCSVI research, is not that it is a simple association or even causation, but that treating (liberating) the CCSVI would treat the MS itself (some have gone so far as to say, cure). Leaving the question of what percent of patients with MS actually have CCSVI (Dr. Zamboni is quoted to have said at some point that he found evidence of CCSVI in 100% of MS patients -- but we know that no diagnostic test -- be it lab, ultrasound or MRI -- is perfect), an open-label study in the Journal of Vascular Surgery was supposed to help lead us in the right direction:

http://www.ctv.ca/generic/WebSpecials/pdf/YMVA_4198_Zamboni_final.pdf

I truly wish their data had been more promising, but in this open-label, uncontrolled trial, they did not meet their endpoints for SPMS or PPMS (there was some QoL [quality of life] improvement) and in RRMS, they did not meet their annualized relapse rate outcome.

If you look at their data (open-label) "Patients free of relapse, %" venoplasty went from 27% to 50% (18 months). Now, if you look at prior clinical trials, such as the AFFIRM (Tysabri vs. placebo) placebo arm, it went from 2% pre-treatment to 60% at year 1 and 46% at year 2.

This highlights that the rate or number of pre-study relapses and in-study relapses, even in an untreated group is different. One of the reasons for this, is that in a clinical trial patients and physicians are more careful about what they call a relapse. So, no matter what you do (unless you are causing more relapses with a dangerous intervention), the number of relapse free patients will go up during a trial.

MRIs were not performed in a standard way at a standard time point and it is very possible that patients enrolled because their disease was somewhat active at that moment in time, and when the MRI was repeated they were not in close time proximity to a relapse.

In terms, of "Patients with MRI Gad+ lesions, %," venoplasty went from 50% to 12% and in the placebo AFFIRM arm, it went from 46% to 32% at year 1 and 28% at year 2.

So, you may be saying -- well this was a small study and it warrants further research with larger numbers of patients in more Centers. This is a good idea, but we are far from what some have called a cure -- there is even a group on FaceBook called "Dr. Paolo Zamboni for Nobel Prize."

So, why wait -- why not go somewhere and get the Liberation procedure performed?




Stanford University recently had 2 patients with very severe adverse events from venous stenting for CCSVI: one patient died from bleeding in the brain (after the procedure you go on blood thinners) and another patient had migration of one of the stents into their heart and required surgery to remove them). Needless to say, these are very concerning adverse events and the surgeon at Stanford will no longer be performing this procedure.




With CCSVI, I was hoping for the best, but please don't allow hope to endanger safety




- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

MS Virtual/SecondLife Town Hall Meeting

Aural Orals

Disappointing baby steps: no surprise.

Merck KGaA and EMD Serono released that the FDA did not accept the NDA submission for oral Cladribine (Mylinax/Movectro) submitted on September 30th 2009.

This ‘Refuse to File’ letter means that the FDA is saving its time by not even reviewing the full NDA submission because of potential flaws in the submission. Under Title 21, CFR (Code of Federal Regulations) 314.101, the FDA must notify the applicant within 60 days of the submission if they will refuse to file (RTF) the application.

This raises several questions:

1. Did the FDA only tell EMD Serono about the RTF on November 30^th 2009? I find it hard to believe that the FDA would hold out until the last day (60 days from 09/30/09). Instead, it seems more likely that EMD Serono knew bout the FDA’s decision earlier than the press release (just as it knew about the disappointing results of REGARD well before it finally released the results).

2. The next step for EMD Serono is to request in writing within 30 days of the date of the agency’s notification an informal conference with the agency about whether the agency should file the application. So, if EMD Serono knew about the RTF letter prior to 11/30/09, then why wouldn’t the company have already requested a meeting with the FDA? (the EMD Serono News Release states that “EMD Serono plans too request a meeting …”)

3. Requesting the meeting is crucial, since the date of filing is reset (and further delayed) for another 60 days. There must, therefore, be a major deficiency in the application – so let’s explore 21 CFR 314.101 (d) and (e).

Under 21 CFR 314.101(d), the FDA ‘may’ refuse to file an application for several reasons, most of which seem unlikely to be the reason for the RTF decision:

Technical reasons:

314.101(d)(1) – The application does not contain a completed FDA form; 314.101(d)(2) – The application is not submitted in the form required under 314.50;

314.101(d)(4) – The applicant fails to submit a complete environmental assessment …;

314.101(d)(5) – The application does not contain an accurate and complete English translation …;

314.101(d)(6) – The application does not not contain a statement for each nonclinical laboratory study that it was conducted in compliance with the requirements set forth in part 58 …

314.101(d)(7) – The application does not contain a statement for each clinical study that it was conducted in compliance with the institutional review board regulations in part 56 …;

314.101(d)(8) – The drug product that is the subject of the submission is already covered by an approved application;

314.101(d)(9) – The application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.

Under 314.101(e), the agency will refuse to file an application or will consider an abbreviated new drug application not to have been received for other technical reasons regarding the drug product itself.

It seems hard to believe that EMD Serono would have made a mistake as simple as not sending three copies (an archival copy, a review copy and a field copy). When I have submitted IND (investigational new drug) applications, I had no problem doing so (although the coloring of the binders is a little confusing).

I believe that the reason for the RTF falls under 314.101(d)(3):

CLARITY is only one trial and an application that only contains one adequate and well-controlled study.

But this is unless agreement to utilize single-control trial with Agency.

So wasn’t this agreement made?

The same could be argued for Acorda’s submission of Fampridine-SR and then the FDA’s briefing to the Central and Peripheral Nervous System Drugs Advisory Committee, although the issues raised in the briefing were recanted by a more senior FDA representative (but this was only after discussion had been ongoing and it is difficult to believe that other members of the FDA team were not aware of the content of the briefing until the Advisory Committee – all analysts and investors were and we discussed it in this blog). So, the FDA may be recanting its previous agreement with EMD Serono to accept an NDA application without 2 trials.

Also, the RTF seems much more serious than the formatting issues and request for more information that Acorda received earlier regarding Fampridine-SR.

The seriousness of the RTF has affected Merck KGaA stock and may allow Novartis’ Fingolimod (FTY720) to overtake Cladribine as the first oral medication for RRMS (Fampridine-SR will be the first oral medication for MS, albeit not disease modifying).

EMD Serono has been delayed by at least 60 days, and if Novartis files (using its two trials – TRANSFORMS and FREEDOMS) with the FDA prior to that, it may be able to be approved prior to Cladribine (or at least around the same time), but the lack of an EMEA application raises the question of when Novartis will file with the FDA.

Patience is key.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org