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