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- Dr. Daniel Kantor, MD
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

MS Town Hall Meeting: Dothan, AL on 11/04/10

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Support Non-Mainstream MS Research ... Vote today!

We are applying for a grant to support a non-mainstream MS Research Institute to support funding for research that wouldn't otherwise have much funding -- CCSVI (chronic cerebrospinal venous insufficiency), LDN (low dose naltrexone) etc.

Vote daily and spread the word at: http://pep.si/dniprs



Please VOTE today and every day:

- Dr. Daniel Kantor, MD BSE Medical Director Neurologique info@neurologique.org www.neurologique.org

ECTRIMS 2010 (Goteborg, Sweden): Living longer with disease modifying treatments

Well, another year has past since our historic first time ever (in any medical conference) live video bloggingat ECTRIMS 2009 in Dusseldorf, Germany. This year, ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) was held on October 13 - 16, 2010 in Goteborg, Sweden and once again I filmed video blogs directly to you.

What made this year special was that aside from interviewing other MS professionals (Dr. Gary Cutter at the Consortium of MS Centers or CMSC Annual Meeting), we had other neurologists make videos with MSWorld, as well. The excitement is spreading and this can only be a good think for people with MS and their families.

For the next few postings, I will highlight important abstracts and presentations.

It is very difficult t wrap our heads around the concept of disease modification, but living longer is something that we can all understand. As Daniel Defoe first wrote in The Political History of the Devil, 1726:"Things as certain as death and taxes, can be more firmly believed." Benjamin Franklin coined the phrase n a letter to Jean-Baptiste Leroy, 1789, which was re-printed in The Works of Benjamin Franklin, 1817: "'In this world nothing can be said to be certain, except death and taxes." In an abstract by Reder et al. entitled: Survival analysis 21 years after the initiation of the pivotal interferon beta-1b trial in patients with RRMS, the authors compared the survival of those originally randomized to Betaseron/Betaferon to those initially placed on placebo; people with MS who were originally placed on Interferon ß-1b had increased survival.

This is significant because no longer do we have to say that this medication may modify the disease course, but that it may actually make you live longer.

This is another reason to start treatment early.

- Dr. Daniel Kantor, MD BSE Medical

Director Neurologique

info@neurologique.org

www.neurologique.org

Ex-U.S. access to Ampyra

On the MSF Focus Ask-the-Doctor forum, I received the following question:

Question

Dear Doctors,

May I ask, when you prescribe the compounded 4-AP for an MS patient, what makes you decide this patient will need a sustained release not an instant release form, and vice versus?

My second question is, suppose a patient is taking Ampyra, if they have to switch to 4-AP, should they take 4-AP SL 10mg/capsule which is very much like Ampyra, or what dose should they start?

I’m a wheelchair MS patient in Vietnam. After a lot of efforts, a friend of mine living in the states managed to buy me one month supply of Ampyra with the cost of $1,271 (Almost all my income last year, the average income in Vietnam is less than $100/month. But I think if I can walk again, it worths it).

As suggested by my neuro, to play safe, I took 1 tablet/day for the first week. My walking ability improved, and so did my bladder problem. However, when I increased dose to 2 tablets/day, everything was getting worst. Now I’m back to 1 tablet/day and in good shape again.

I’m very happy with the effect, however I cannot afford another month of Ampyra and really want to switch to 4-AP. My neuro refused to write a prescription for it, though, saying it’s illegal in Vietnam, also he can’t prescribe for something he’s not sure about quality. He promised to talk to the authorities about having a GMP, GSP… (I’m not sure about this bit) pharmaceutical company here compounded it for MS patients. I know my neuro is a man of his words, but it will take several years before they can make their decision, and I can’t wait that long…

Fighting with MS is hard enough, it’s even harder for me in Vietnam with limited MS medication and experience. I feel so lonely and abandoned joining forums here and see people discussing about a wide range of medication they can choose

Sorry I didn’t mean to moan. It’s just pouring out.

I’m appreciated for your inputs.


Answer

We certainly all feel for your situation. Was it your doctor who has been corresponding with me? If so, I can attest to the amount of time that he has invested in helping you. We worked with Biogen Idec (they handle Ampyra globally, ex-U.S., for Acorda), but unfortunately the "named" program is not available in Vietnam.

Ampyra is a pharmaceutical grade product and there are several reasons to choose it over Compounded 4-Aminopyridine, including the potential for compounding/dosage errors with potential for overdose and resultant seizures. Please see my discussion: http://bit.ly/dzVLcP

You are right (as most patients are) that some people feel worse on 10 mg every 12 hours than 10 mg once a day. Patients with kidney problems need to watch out for reduced renal clearance of Ampyra, which can cause an increase in the amount of Ampyra in the body, and result in seizures. The FDA has asked Acorda to study 5 mg pills, but it may not be that easy to make. Compounded 4-Aminopyridine can, of course, be made in 5 mg capsules.

You are not moaning, you are frustrated, but hopefully people with MS in the U.S. and Europe can learn from you that, in some ways, things are easier in the Western World (that might not be a consolation to many) -- but, rest assured, your neurologist and I are in contact.


Stay strong.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Gilenya vs. Cladribine: Differences and similarities in regulatory review

Pharmawire covered our comment, see below:

Novartis: Recent Gilenya decision best-case scenario; cladribine receives two-year label restriction in Australia - physicians Pharmawire

Novartis' (NYSE:NVS) Gilenya is expected to take more market share than previously expected in multiple sclerosis, due to labeling that was a "best case scenario" for the company, neurologists said. Gilenya (fingolimod) 0.5 mg daily received approval today, making it the first oral multiple sclerosis drug approved in the US. Competitor Merck-Serono is awaiting an FDA ruling on their competing oral compound cladribine, later this year. Under the label restriction in Australia, Merck-Serono's Movectro (cladribine) is indicated for the treatment of relapsing-remitting multiple sclerosis for a maximum duration of two years. Elmar SchNee, Head of Pharma at Merck KGa, said at a recent investor conference that cladribine faces an upcoming EU decision, and the regulators might be "more restrictive" there, following on from comments about the recent 2-year Australian label restriction. Cladribine tablets will be registered in Australia under the trade name Movectro. "I am extremely pleased Gilenya got approved, and pleased that the FDA didn’t put a lot of restrictions on it, as those decisions are best left to physicians," said Dr Anne Cross, a professor of neurology at the Manny and Rosalyn Rosenthal – Dr. John Trotter MS Chair in Neuroimmunology at Washington University in St. Louis. Cross said she will initially use Gilenya in patients who have failed the front-line therapies, but expects to use the drug in other patients after the drug has been on the market for awhile. "I'm a conservative person, so I tend to not use new drugs in a lot of patients until after a few months," she said. However, while Cross is excited about the potential of cladribine due to its more convenient dosing schedule relative to Gilenya, she said the drug is "a problem if you need to reverse it." She explained that cladribine is long acting, therefore if patients develop infections, "you’re in a bind. It isn’t reversible. That worries me a little bit about cladribine, moreso than Gilenya," Cross said. There are some individual things that will be “ironed out” with Novartis' drug, such as how closely to monitor heart rate, but this issue should “sort itself out over time,” Cross noted. "There is a lot of demand for Gilenya. Novartis really got a deal from the regulators. It’s going to do a lot for their market share," said Dr Samuel Hunter, a neurologist and President of the Advanced Neurosciences Institute in Franklin, Tennessee. He added that he was surprised that the drug did not receive a blackbox warning due to several malignancies that were observed in clinical trials. Still, Gilenya was likely spared such a warning since while there was an increased risk for the development of malignancies in the Phase II TRANSFORMS study, which tested the 0.5 mg and 1.25mg doses of Gilenya, in the larger Phase III trial, involving over 1,000 patients, there was no increased risk, noted Dr Douglas Jeffery, a neurologist at Wake Forest University School of Medicine. In addition, there was also no increase in cancer risk in patients who entered into the long term extension study, he said. There is a risk management program, and both the company and physicians will continue to evaluate the safety of Gilenya, Jeffery noted. Jeffrey also cautioned that despite Novartis' seemingly easy approval process and label for their oral MS drug, Merck-Serono's cladribine and its side-effects are at a different order of magnitude in regards to malignancy risk. Based on the literature in hairy cell leukemia, patients who received lower doses of cladribine than those used in MS trials, reported secondary malignancies. "This is a whole different order of magnitude, which the FDA will have to look at very carefully," he said. Hunter added that despite the ease for Novartis in securing approval, he also believes that the FDA will follow guidelines from the EU and Australian regulators with regards to cladribine and its label restriction. "The agency is going to be cautious, since the drug is too similar to other immunomodulators that have had problems in MS," he said, referring to Biogen’s Tysabri. However, a risk management program is easier to follow for an oral drug, he noted. The risk management plan for Gilenya is very benign, said Hunter, who has the in-house skills to handle those tests internally at his clinic. "We have a retinal scanner that can do the job for the eye test. Most neurologists have an EKG machine. That’s manageable for most people who are treating MS," he said. The risk management program for Gilenya requires that patients receive a medication guide, and a letter and safety information guide for healthcare providers. Novartis will also be initiating a five-year, international post-authorization safety study to monitor selected safety-related outcomes and a voluntary pregnancy registry. Dr Daniel Kantor, a neurologist and Medical Director of the Neurologique Foundation in Florida, said the label for Gilenya was the best possible outcome for Novartis. The addition of an indication for disability is probably the most important indication for MS in a long-time, he said. That combined with the fact that it is an oral drug for delaying disability progression is sure to increase market share, he noted. The REMS program for Gilenya was also very beneficial to Novartis, and will be clarified further in the upcoming weeks, Kantor said. by Kimberly Ha

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

Pharmawire quotes Dr. Kantor on Gilenya launch

You heard it here first.

Please see the Pharmawire article below:

Novartis' new oral MS drug Gilenya official US launch date 4 October, company confirms Pharmawire

Novartis (NYSE:NVS) plans to launch its new oral multiple sclerosis (MS) drug Gilenya (formerly Gilenia) on 4 October, according to Dr Daniel Kantor, Medical Director, Neurologique Foundation in Florida. A spokesperson for Novartis confirmed that in the US, physicians will be able to prescribe Gilenya starting on 4 October 2010. Gilenya is the first oral disease-modifying therapy for the treatment of relapsing remitting multiple sclerosis (MS). The company will be hosting an upcoming internal launch meeting in Orlando, Kantor said. Novartis also plans to host a web conference with physicians to discuss this new treatment on 7 October, he noted. by Kimberly Ha

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

Rocking MS: First Big News since Betaferon, GA and Tysabri hit the market: Open Letter to Novartis CEO

Open Letter to Joe Jimenez, CEO, Novartis:

Dear Joe,

CONGRATULATIONS!

The FDA Approval of Gilenya(TM) is a milestone in the MS community.

Novartis (NVS) heard the outcry from MS patients, care partners, nonprofits and neurologists; Novartis heard the outcry and listened carefully.

What makes the approval even more exciting is that Gilenya(TM) [FTY720, Fingolimod, Gilenia] is approved for reduction in relapses and in slowing disability progression. While Gilenya is approved for relapsing MS, we are excited about the potential that Gilenya may hold in progressive forms of MS as well (and we await the conclusion of the PPMS trial).

The REMS (Risk Evaluation and Mitigation Strategy) is gentler than we ever could have expected, but this will of course be further clarified in the future.

Novarti's press release was at 7:00 AM CET (GMT +1) and we first broke the news less than 30 minutes later:

http://bit.ly/cOemMl

http://bit.ly/cwMe4W

http://bit.ly/cSNqey

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

Brave New World: Oral Medicines in MS

In a few hours, the U.S. FDA (Food and Drug Administration) is set to make history by approving the first oral medication for the reduction of annualized relapse rate in Relapsing forms of MS.

It is unlikely that the FDA will delay this milestone in MS therapeutics, and so Novartis's FTY720 (Fingolimod) will be welcomed to our growing MS armamentarium. It is unclear what the name of this medication will be -- please see: http://bit.ly/aqTrsz (will Gilenia be spelled "Gelenia" or "Gelinia" or "Gelenea" or "Gelinea").

Of course predictions of how MS specialists and general neurologists will use this medication, are usually discussed in private consultations with Wall Street analysts/investors, but I thought that it would be useful to discuss different patient types and where FTY720 may be positioned in their care:

1. Clinically Isolated Syndrome (CIS) -- FTY720 has not been systematically studied in CIS, and so there will be no FDA indication for its use in the first demyelinating event suggestive of MS. In the future, however, FTY720 may be studied, just as EMD Serono's Cladribine is (ORACLE MS - Oral Cladribine in Early MS). Novartis will probably wait some time before initiating a large scale CIS trial, just as the other DMD companies did (CHAMPS, ETOMS, BENEFIT, PreCISe).

2. Early MS -- Patients and their physicians will weigh the benefits of an oral medication as well as the patients' desire to not be on injectable medications, against the long term safety data of the currently approved injectable MS treatments.

3. Newly diagnosed -- When faced with options of an oral medication or injectables/intravenous (IV) medications, patients may be swayed to choose the oral treatment because of fears concerning the older medications and a perception that oral means safer (this is not necessarily borne out by the safety data).

4. Active RRMS -- People with active inflammatory MS will need an additional option to control the demyelinating lesions, and FTY720 will afford another option. Patients and their neurologists will choose between Biogen Idec's and Elan's Tysabri (natalizumab) and FTY720. Other patients who have been on every DMD, will only have FTY720 to choose from.

5. MS patients who have not tolerated other MS medications -- FTY720 will allow an additional medication option for those who cannot be on the other DMDs because of tolerability issues.

6. Early secondary progressive MS -- Although not studied in TRANSFORMS or FREEDOMS, there is an ongoing trial of FTY720 in PPMS (primary progressive MS). If the suggestive animal data translates into human beings, then FTY720 could be effective in both RRMS and PPMS, which would make it an attractive drug for SPMS.

7. Later secondary progressive and primary progressive MS -- Although not studied in TRANSFORMS or FREEDOMS, there is an ongoing trial of FTY720 in PPMS (primary progressive MS). If the suggestive animal data translates into human beings, then FTY720 could be effective in PPMS (and perhaps later SPMS).

8. Patients in the FREEDOMS II trial -- Patients who are enrolled in the ongoing placebo-controlled trial of FTY720, may be tempted to drop out and initiate FTY720, instead of taking the risk of placebo. This drop-out rate plus the approval of FTY720 may cause the Data Safety Monitoring Board (DSMB) to cut FREEDOMS II short.

9. Patients in other MS clinical trials -- Patients may choose to start this new oral medication instead of taking the risk of placebo in other trials. This could have a chilling effect on ongoing MS research.

As you can see, there are many potential uses for FTY720, but most importantly it will be AVAILABLE.

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

Open Letter to Dr. Zorba Paster -- Dangerous Assumptions and RLS

Dear Dr. Zorba Paster,

While I appreciate your patient-centered approach to medical queries on your radio show, as a neurologist I was very concerned to hear how you answered a question regarding nonspecific nighttime leg symptoms. On September 12, 2010, a caller asked about her uncomfortable leg sensations. Without a complete history or physical examination, you informed her that she has restless legs syndrome (RLS) and should ask her doctor to place her on Requip(R) (Ropinirole). Not only is this favoring one medication over others. You did not encourage the patient to look for the source of her symptoms, for example if this is truly RLS, iron deficiency should be looked for.

Most concerning, it is unclear that this patient even has RLS. There are many other causes of nonspecific nighttime symptoms, such as spasticity, peripheral neuropathy, skin disorders etc.

I am concerned because this patient may have then gone primary care physicians and told her that she has RLS and needed to be on Requip(R). This unexpecting physician, may have taken the diagnosis as an established one and not investigated it fully, nor treated it appropriately. This patient may have then had the rare side effect of suicide, all because she was on an unneeded medication.

Once again, I implore you to stick to your excellent expertise and comingling of CAM (complementary and alternative medications) and approaches because whenever you make an assumption and recommendation outside your specialty area, it raises doubt over all your other answers.

Please remember, Primum Non Nocere (First Do No Harm).

Thank you,

Daniel Kantor, MD BSE
Medical Director
Neurologique

President-Elect
Florida Society of Neurology

CCSVI and the MSF

As many of you know, I answer questions on the MSF forums (Ask the Doctor and African Americans with MS), and I wanted to share a recent question and answer.

Question:

I am 45 year old American woman with rr ms. i am pretty stable, have drop foot, fatigue. I read that the CCSVI could block the illness and improve symptoms. Of course I am curious. My family urges me to wait until there is more solid evidence of success. How long should I wait? If I can find a doctor here in Italy (I live in Italy) who is willing to do the angioplasty I think I would do it tomorrow. It seems to be helping the many who have done the procedeure. Isn't this evidence enough? What are the major cons?

Answer:

Thank you for the question.

CCSVI (chronic cerebrospinal venous insufficiency) is the name of the proposed condition, not the procedure -- which has been termed the Liberation Procedure, and is venoplasty with or without stenting.

A few previous blogs of mine on this, can be found at:

http://bit.ly/cTdVQJ

http://bit.ly/axiQKn

http://bit.ly/9HuOj1

http://bit.ly/d46R7r

http://bit.ly/cosb6g

So, what does this all mean?

The testimonials and videos of people with MS undergoing venoplasty are impressive, but so is the response of people in clinical trials, of medications which may ultimately found to not be effective overall.

On the other hand, people with MS don't want to wait until the procedure is either proven or disproven; this is why we are designing research where everyone still gets the procedure, but at least we collect useful information that will help the entire MS community in the future ... so stay tuned for the research.

In regards to "evidence enough," sadly the answer is no. Scientific evidence is a process that has rules and processes. Suggestive - possibly, hopeful - definitely, but evidence has a very specific meaning.

Thank you,

Daniel Kantor, MD BSE

Medical Director

Neurologique

President-Elect

Florida Society of Neurology

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Virtual Second Life MS Town Hall Meeting

Virtual Second Life MS Town Hall Meeting:

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

Heat and MS

Now that the summer is sizzling hot (warmer up North than here in Florida), we received the following question:

Question

I live in NJ but our temps soared to 105 and 107 this week. I have had MS (diagnosed) for 5 years. We lost a/c at work this week, and I had a scary episode that almost put me into the emergency room. I drove home (and it's hotter in the car) and luckily my husband was with me.
I suddenly said "I don't feel well" and got instantly dizzy, almost blacking out and vomiting. I lay on the floor of the bathroom like that for a half hour. Called the doctor who said if I didn't improve in two hours to go to the emergency room.

I'm a patient at the Gimble center in Teaneck and my check up is in two weeks. I guess I will get a note stating that when we lose a/c or heat I need a phone call because i can't work under those conditions. I I immediately drank 5 or so glasses of juice and water.

Any other suggestions would be appreciated. I had some cool packs from my COPAXONE deliveries and I put them on my body especially on my wrists and under my armpits.

It was very scary for me, I hope it never happens again.

Answer

Thank you for the email.

As you are well aware, heat affects people with MS a lot and can cause an uncovering of older symptoms (this is called Uhthoff's phenomenon).

You made the right choice of using your COPAXONE cool packs, but there are more formal cooling vests, from such companies as Polar Products and Steel.

Two MS organizations work hand-in-hand have assistance program for people with MS who need these vests -- the MS Association of America (MSAA) and the MS Foundation (MSF). We work closely with both of these great trusted partners and Dr. Kantor serves as a member of MSF's Healthcare Advisory Panel and answers questions on their MS Forums:

http://bit.ly/9irjfl


MSAA - http://bit.ly/bb4poe
MSF -- http://bit.ly/c92L1l
Neurologique -- http://bit.ly/a9o5va

There are two main types of cooling vests: active and passive.

Active cooling involves a power source and are less common than
passive cooling. Passive cooling mostly mean evaporative cooling
(the vests or hats or scarves, etc.,which have beads inside,
that you dip into water) and ice pack cooling.

It is important to use the right cooling vest for your environment
and for YOU.
For example, in high humidity areas evaporative cooling is not the right
choice and ice packs (like you used are better).
Here is another source of information: http://bit.ly/bIRxo0 


I hope that this was useful.



Follow-up

I just spoke to my boss who knows now to call me if the a/c ever breaks. This is what my doctor recommended. He says it's not even a "reasonable accomodation" because it's simply the civil, correct way to go. When I go to Gimble next week however, I'll have my neurologist put it in writing that if the heat or a/c breaks, I need a phone call.

Has anyone else faced a similar situation? How did your employer react?

Post to Facebook: http://bit.ly/bCwjf2



- Dr. Daniel Kantor, MD BSE
Medical Director Neurologique

info@neurologique.org

www.neurologique.org

Happy days at the FDA

Happy Days are here again.

June 10^th 2010 is a big day for the MS community – the FDA (Center for Drug Evaluation and Research (CDER)) is having a Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee to discuss Gilenia (Fingolimod or FTY720) .

Although Novartis’s Gilenia, which is set to be the first oral disease modifying agent/drug/therapy (DMA/DMD/DMT) for Multiple Sclerosis (MS) had its priority review PDUFA (Prescription Drug User Fee Act) date pushed out to September 2010, this meeting is important because it will give us much clearer insight into what concerns the FDA may have.

The are 12 questions raised to the FDA Advisory Committee to discuss are:

1. Has the sponsor demonstrated substantial evidence of effectiveness of fingolimod for the treatment of patients with relapsing remitting multiple sclerosis to reduce the frequency of clinical exacerbations? [Voting Question]

2. Has the sponsor demonstrated substantial evidence of effectiveness of fingolimod for the treatment of patients with relapsing remitting multiple sclerosis to delay the accumulation of physical disability? [Voting Question]

3. If the answer to question #1 and/or question #2 is yes, should the sponsor be required to evaluate the effects of doses lower than 0.5 mg once daily? [Voting Question]

4. If the answer to question #3 is yes, should this be required prior to approval? [Voting Question]

5. If substantial evidence of effectiveness has been demonstrated, do you conclude that there are conditions under which fingolimod could be considered safe in use for this indication? [Voting Question]

6. First-dose effects of fingolimod include bradycardia and heart conduction abnormalities. Based on the data presented to you, should patients be required to receive the first dose in a monitored setting? [Voting Question]

7. If the answer to question #6 is yes, should that requirement apply to all patients or to a specific subset?

8. Fingolimod causes macular edema, including at the dose proposed for marketing (0.5 mg). Is routine ophthalmic examination sufficient to monitor patients treated with fingolimod? [Voting Question]

9. Fingolimod causes a gradual decline in pulmonary function that appears partially reversible. Do you believe that routine pharmacovigilance will be sufficient to mitigate the risks associated with the pulmonary toxicity of fingolimod? [Voting Question]

10. If the answer to question #9 is no, what additional monitoring or study do you recommend?

11. The sponsor has proposed to conduct a 5-year post-marketing safety study in 5000 patients to further explore the safety of fingolimod 0.5 mg under routine clinical care. Do you believe that such a study would be sufficient to address safety issues observed in this database, or do you believe that other safety studies should be required to assess specific safety concerns? If so, please identify these concerns.

12. Considering the risks and benefits, do you believe that fingolimod should be generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy? [Voting Question]

To help us sort through these question, let’s go through the poster abstracts presented at the recent Consortium of MS Centers (CMSC) Annual Meeting in San Antonio, TX.

1. 1 1. TRANSFORMS – Oral fingolimod (FTY720) vs intramuscular (IM) interferon beta-1a (IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS): clinical efficacy results.

In this trial patients received a daily oral pill and a weekly intramuscular injection, but it was double-blinded (both the patient and the team evaluating the patient) didn’t know whether she was receiving a real pill of fingolimod (at two doses – 0.5 mg and 1.25 mg) and fake (placebo) intramuscular injections or a placebo pill and real interferon beta-1a (Avonex) intramuscular injections.

The 3 arms of the study were well matched before the study and we saw a significant reduction in the annualized relapse rate (ARR) in this one year study: ARR for fingolimod 0.5 mg was 0.16 vs. fingolimod 1.25 mg at 0.2 and IM IFNB-1a at 0.33.

This means that we have a study population that looks similar to our more recent (“modern”) clinical trials in that it shows an ARR for the current injectables at about 0.33, yet we have an oral drug that beats active treatment (not simply placebo – this trial had no oral placebo + IM placebo arm) by 38 – 52%.

The data was further divided into the ARR for treatment naïve patients (0.15 vs. 0.17 vs. 0.31) and the ARR for participants who were previously treatment with a DMT (0.26 vs. 0.33 vs. 0.53). This makes a lot of sense – people who entered the study with 1 or more confirmed relapse during the previous year (or 2 or more confirmed relapses in the previous 2 years) and who had been on a DMT already, are more likely to have not responded fully to the DMT and, hence, be harder to treat with any medication, including fingolimod.

Now many patients (and neurologists) will say that an ARR of 0.33 (in patients treated with the current injectables) does not reflect the relapse rate they see in real life, so the investigators looked at he ARR for all relapses (not simply confirmed, but also unconfirmed) and that was 0.3 vs. 0.33 vs. 0.63. So, even if we liberalize the definition of a relapse, fingolimod still significantly beats Avonex in this one year trial.

Instead of looking at the relapse rate, we can also look at the proportion of participants relapse-free (after all, isn’t that what we want?) and that comes to 83% vs. 80% vs. 69%.

Not all relapses are created equally

While relapses are important, the disability they are accompanied with (not just left with) are important – so we care about the severity of the relapses as well. Although not approved by the FDA for these purposes, I believe that our DMTs not only reduce the number of relapses but also their severity. Looking at relapses requiring hospitalization, the ARR for the three groups (fingolimod 0.5 vs. fingolimod 1.25 mg vs. Avonex) was 0.022 vs. 0.039 vs. 0.077; this means that you are 71.4% less likely to need hospitalization for a relapse if you are on fingolimod 0.5 mg as compared to Avonex (49.4% for fingolimod 1.25 mg vs. Avonex).

In the RECLAIM (Relative Efficacy of repeat Course of intravenous methyLprednisolone and intramuscular ACTH in the treatment of acute relapse of multiple sclerosis after sub response to Initial course of intravenous Methylprednisolone), we (this is a Neurologique specific trial written by Dr. Kantor) are trying to see how we can reduce the need for additional courses of steroids for the treatment of MS and in the TRANSFORMS trial, taking fingolimod meant that even if you had a relapse, it was less likely that you needed steroids (ARR of 0.084 vs. 0.115 vs. 0.176).

So, of the 429 participants on fingolimod 0.5 mg vs. 420 on fingolimod 1.25 mg vs. 431 on IFNB-1a, 17.5% vs. 19.5% vs. 29.9% had a relapse and 11.2% vs. 13.1% vs. 18.3% required steroids with no hospitalization and 1.9% vs. 3.1% vs. 7% required hospitalization.

In summary, the efficacy data from TRANSFORMS (Trial Assessing Injectable Interferon vS FTY720 Oral in Relapsing-Remitting Multiple Sclerosis), demonstrated that in a one year trial, fingolimod significantly beat a currently available injectable in terms of measures of relapses. The results for fingolimod 0.5 mg vs. 1.25 mg, has led us topursue the lower 0.5 mg dose rather than 1.25 mg.

2. 2. Oral fingolimod (FTY720) vs placebo in relapsing-remitting multiple sclerosis (RRMS): 2 year efficacy results of the phase III FREEDOMS trial.

While TRANSFORMS [2302] was a one year global (including U.S.) trial comparing two dose of fingolimod to active treatment (Avonex), FREEDOMS was a two year global (ex-U.S.) trial comparing two doses of fingolimod to placebo.

As we have discussed in the past (http://bit.ly/98pGyk and http://bit.ly/dBWxrH), FREEDOMS [2301] (FTY720 Research Evaluating Effects of Daily Oral Therapi in Multiple Sclerosis) confirmed in a longer (2 year) trial that fingolimod has robust efficacy. Compared to placebo, fingolimod 0.5 mg and 1.25 mg reduced ARR by 54 – 60% (and it did so whether participants had been previously treated with a DMT or no). Compared to placebo, fingolimod 0.5 mg and f

Fingolimod 1.25 mg increased the proportion of participants who were relapse free (46% vs. 70% vs. 75%).

It’s not all about the relapses – what about disability?

Fingolimod significantly reduced the risk of disability progression by 30% – 40% (we look at 3 or 6 month confirmed Expanded Disability Status Scale or EDSS progression and the Multiple Sclerosis Functional Composite or MSFC).

3. 3. Oral fingolimod in relapsing-remitting multiple sclerosis (RRMS): MRI findings from TRANSFORMS and FREEDOMES phase III trials

So, now that we have seen the robust clinical efficacy (in terms of relapses and also some disability data) from TRANSFORMS (fingolimod vs. IM IFNB-1a) and FREEDOMS (fingolimod vs. placebo), we move on to the best (yet imperfect) surrogate marker we have, MRI.

When using MRI to compare the efficacy of treatments, we look at several aspects of the MRI – inflammatory lesions (there is Gadolinium enhancement of white matter spots when there is active breakdown of the blood brain barrier; T2 lesions are the white spots we see that do not necessarily have enhancement at this point in time, but must have at some point) in terms of number and volume, as well as loss of brain volume (atrophy).

New/newly enlarged T2 lesions (‘white spots’):

In TRANSFORMS, there was a 31% - 42% reduction on the mean lesion count as compared to IFNB-1a and in FREEDOMS it was 74% as compared to placebo.

Gadolinium enhancing (Gd+) lesions:

In TRANFORMS, after 12 months, there was a mean of 0.5 Gd+ lesions in the IFNB-1a arm vs. 0.2 in fingolimod 0.5 mg and 0.1 in fingolimod 1.25 mg.

In FREEDOMS, after 24 months, there was a mean of 1.1 Gd+ lesions in the placebo arm vs. 0.2 in both fingolimod arms.

Another way of looking at this, is that in TRANSFORMS, the percentage of patients free from Gd+ lesions was 80.8% on IFNB-1a, 90.1% on fingolimod 0.5 mg and 91.2% on fingolimod 1.25 mg. There was no statistical difference in the percentage of participants free from new/newly enlarged T2 lesions (45.&% vs. 54.8% vs. 48%). In FREEDOMS, 65.1% of participants on placebo were Gd+ free compared to 89.7% on fingolimod 0.5 mg and 89.8 on fingolimod 1.25 mg. There was also a statistical difference in the percentage of participants with new / newly enlarged T2 lesions – 21.2% in placebo vs. 50.5% in fingolimod 0.5 mg and 51.9% in fingolimod 1.25 mg.

Looking at the data together, it argues how similar TRANSFORMS and FREEDOMS were and it explains why there was no statistical difference in the percentage of participants with new / newly enlarged T2 lesions in the three arms of the TRANSFORMS trial: namely, because the IFNB-1a arm also had an almost 50% of participants with no new or newly enlarged T2 lesions (as compared to 21.2% in the placebo arm of FREEDOMS).

It is not surprising, then, that there was less change (accumulation) of T2 lesions from baseline in the fingolimod arms as compared to placebo (in FREEDOMS) and not as compared to IFNB-1a (in TRANSFORMS).

Not just accumulation, but loss

We are not only interested in T2 lesions, but in T1 hypointense lesions (unfortunately termed ‘black holes’) and brain volume.

In FREEDOMS, the mean change from baseline in T1 hypointense lesion volume was 50.7 in placebo vs.8.8 in fingolimod 0.5 mg and 12.2 in fingolimod 1.25 mg. In TRANSFORMS, there were only nonsignificant trends in favor of fingolimod over IFNB-1a.

In terms of brain volume, all of our brains lose volume (0.2-0.4% per year) over time (just as the rest of our body shrinks), but this can be accelerated in MS. One of our goals is to slow down any loss of brain volume. In TRANSFORMS, the percentage change in mean brain volume from baseline was -0.45 for placebo vs. -0.31 in fingolimod 0.5 mg and -0.3 in fingolimod 1.25. Probably since FREEDOMS was one year longer, the numbers are higher and the change for fingolimod 0.5 mg was -0.84; for fingolimod 1.25 mg it was -0.89 and for placebo it was -1.31. In FREEDOMS, fingolimod significantly reduced brain volume loss at 6, 12 and 24 months, compared to placebo.

Now, let’s move on to the elephant in the room: safety.

4. 4. Oral fingolimod (FTY720) in relapsing-remitting multiple sclerosis (RRMS): safety findings from TRANSFORMS and FREEDOMS trials.

When choosing a disease modifying agent with your neurologist, we usually consider efficacy (how strong it is), safety, tolerability, convenience and whether the medication will fit into your lifestyle (i.e. whether you will actually take it). The strongest medication in the world is of little use if it is not actually getting into the body.

When TRANSFORMS came out, many of us were concerned with the possibility of safety issues. We clearly have a drug that is effective (it beat one of our current injectables), but the question was the side effect profile. Then FREEDOMS came out and looked more promising. In this poster, we look at the combined safety information.

Firstly, overall less people discontinued the study who were on fingolimod 0.5 mg (8% in TRANSFORMS and 13% in FREEDOMS) than on fingolimod 1.25 mg (13% in TRANSFORMS and 23% in FREEDOMS), or the control arms (IFNB-1a in TRANSFORMS at 11% and placebo in FREEDOMS at 21%).

In clinical trials when you look at the percentage of people who have any adverse event (AE) it is always high, but the serious AEs (SAEs) are what concern are much more.

The overall incidence of AEs were similar for all the groups (91 – 94 %), except the TRANSFORMS fingolimod 0.5 mg where it was 86%.

AEs that led to discontinuation were more likely in the fingolimod 1.25 mg group (10% in TRANSFORMS and 14.2% in FREEDOMS). Of the IFNB-1a group in TRANSFORMS, 3.7% had any AE that led to discontinuation and in FREEDOMS the placebo arm had 7.7% while the fingolimod 0.5 mg arm had 7.5%. The reason for the higher percentages of those who discontinued in FREEDOMS as compared to TRANSFORMS was that it was one year longer.

Death:

In FREEDOMS, 2 participants died in the placebo arm.

In TRANSFORMS and FREEDOMS, 3 participants in the fingolimod 1.25 mg groups:

A. Disseminated varciella zoster virus infection (chickenpox all over the body)

B. Herpes simplex encephalitis (brain infection with herpes)

C. Suicide

Neoplasms

In TRANSFORMS, there were 10 localized skin cancers (8/10 diagnosed at the first on-study examination by a dermatologist 4 - 12 months after enrollment) and all were successfully excised. Breast cancer was reported in 2 patients in each fingolimod groups (3 cases were diagnosed within 4 months of starting study drug and one after 11 months on-study). In the IFNB-1a group, one patient had basal cell carcinoma and one had squamous-cell carcinoma.

After these results, neurologists were concerned and we waited with (a)bated breath for the neoplasm safety data from FREEDOMS.

In FREEDOMS, malignant neoplasms were observed in 4 patients receiving fingolimod 0.5 mg (4 basal cell carcinoma), 4 receiving fingolimod 1.25 mg (1 basal cell carcinoma, 1 malignant melanoma, 1 Bowen's disease [squamous cell carcinoma in situ] and 1 breast cancer) and 10 receiving placebo 3 basal cell carcinoma, 1 malignant melanoma, 3 breast cancer, 1 endometrial cancer and 1 cervical carcinoma in situ).

Other adverse events of special interest: macular edema, bradycardia, first and second degree AV (heart) block, increased blood pressure, liver abnormalities, pulmonary function and infection.

5. Oral fingolimod (FTY720) vs placebo in relapsing-remitting multiple sclerosis (RRMS): baseline data from a 2-year phase III trial (FREEDOMS II [2309]).

This mostly North American study has more safety monitoring than FREEDOMS and is also a two-year trial (last patient completing the trial should be March 2011) and there was intensive safety monitoring for the first several hundred participants and this has been presented to the FDA.

This poster demonstrated that the baseline demographics and characteristics of the three arms in this trial (placebo, fingolimod 0.5 mg and fingolimod 1.25 mg) are similar to each other. This means that we have a well designed population with a good study population, so the results should be valid ... we will wait until after March 2011 ...

... but will this be relevant if Gilenia is FDA approved before the conclusion of FREEDOMS II?

Is it still ethical to continue the trial once Gilenia is FDA approved?

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org