MS Town Hall Meetings: Spreading the Word

After watching the recorded WebTV MS Town Hall Meeting from Orange Park, FL on 03/27/2012, we received the following kind message:




Dr. Kantor,

I did want to take a second to give you some MAJOR kudos on the town hall meeting this past tuesday night. What an awesome talk, that I wish more people from NW Florida were involved in. It was very enlightening to hear questions from both newly diagnosed PTs as well as those who have been living with MS for years. If you're ever in the NW FL area giving a talk like this, please reach out to me and let me know as I'd love to attend. I'd also like to offer myself up for any technical assistance you may need while giving such talks in the area. I'm always willing to devote time and energy towards those pushing to find a cure and engaging the general public about MS education issues.

Once again, great job and I look forward to many more. On a side note, I believe you should ask that all new patients sent your way watch at least one town hall meeting to understand the basics about MS. The talk was VERY educational for sure!

---

... thank YOU for tuning in!

Here are the individual notes from the meeting:





- Dr. Daniel Kantor, MD
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Another reason to quit smoking

The Associate Press reported on a new anti-soking campaign by the CDC -- but there was an unfortunate medical error. Please see below:


Dear Mr. Stobbe and Mr. Felberbaum,

I read with great interest your story: CDC launching graphic anti-smoking ad campaign and I thankyou for covering this important issue, however in the caption to the image, it incorrectly states that: "This image provided on Wednesday, March 14, 2012 by the Centers for Disease Control shows Shawn Wright who had a tracheotomy ...." The image is of a man with a stoma after a laryngectomy and NOT a tracheostomy. While this may not sound like a significant difference to you, it is crucial to the goal of the CDC campaign, which is to be shocking and to educate the Public. A better description would be that this man had a total laryngectomy which is not only something shocking to look at, but also a major complication of chronic tobacco use. A one sentence description that said the man's voice box had been removed would have been sufficient in combination w the sentence at the end that said he speaks and breathes through his neck. [A tracheostomy is simply a tube that allows a direct airway through the neck/trachea as opposed to breathing through the mouth. It is also known a laryngotomy -- while a stoma involves a laryngectomy, which is removal of the larynx and not simply an opening].

I believe that it behooves you to make a clarification/correction to this issue and a follow-up story would be very useful to increase awareness and it would allow you to educate the Public and serve a greater good. I would be happy to work with you on this.


Thank you,

Daniel Kantor, MD
Medical Director
Neurologique

President
Florida Society of Neurology


The AP was very responsible and issued this statement:

ATLANTA (AP) _ In a story March 16 about an anti-smoking advertising campaign, The Associated Press, relying on information from the Centers for Disease Control and Prevention, erroneously reported what kind of medical procedure Washington state resident Shawn Wright underwent. The CDC said Monday that the hole in Wright's throat resulted from a laryngectomy _ the removal of his voice box _ not a tracheotomy.

Comments on FDA's draft guidelines for biosimiliars

This is the second article in the series on Dr. Kantor's comments on biosimilars and regulatory agencies (the first article concerned the European perspective).

Rituparna Chatterjee of the Economic Times published an article titled Biosimilar products development gets a USFDA norms boost but due to editorial constraints, Dr. Kantor's comments were not included. Below you will find the reporter's questions (green) and Dr. Kantor's responses:

"The FDA has a very low threshold that is going to make it very easy to compete in the market."

1. Why do you think this is so?

2. Do giants like Genetech and Biogen stand to gain the most or smaller companies?

3. What does this mean for companies in the space in countries like India/China, etc.?

1. Although the EMA guidelines have been out for a little longer, the FDA was being tight lipped on what their draft guidelines would be. These guidelines set a low clinical bar to demonstrating bio similarity to a reference compound. The question has always been whether a biosimilar would need to do lengthy and expensive clinical testing or whether in vitro (test tube) and preclinical (animal) studies would suffice. The draft guidelines allow for much (but not all) of the testing to be done without the need for large clinical trials. There is an issue, however, of interchangeability vs. biosimilarity -- but it is not entirely clear whether this will be meaningful to payors (and this ultimately drives profits, sales and stick prices). Additionally, biosimilars are allowed to use different formulations from the reference products, thus allowing for more flexibility. These guidelines allow for a case by case analysis and this may give an advantage to certain manufacturers and there is not necessarily a great need to demonstrate clinical biosimilarity in all indications.

2. Giants, like Roche (Genentech has been subsumed by Roche) have built their portfolio in biosimilars, and increased competition may hurt their sales. Analysts have been expecting these draft guidelines for some time, and because of this the stick prices have already adjusted for the lack of perpetual growth. Many of Roche's products continue to have market exclusivity so sales are not expected to be affected for some time (also it will take time for the biosimilars to conduct their studies). There is also the issue of some market exclusivity for the first biosimilar that comes to market, and some companies may be better than others at getting this going.

Other companies, such as Biogen Idec may benefit and be threatened by these new draft guidelines, because it will allow them to both produce their own biosimilars of others' reference products, but also have biosimilar companies produce their branded products, such as Avonex, Tysabri and Rituximab (in collaboration with Roche). Biogen already has the capacity to produce beta interferons for multiple sclerosis (MS), and they could theoretically produce biosimilars of Bayer's Betaseron (and Novartis's Extavia) and EMD Serono's Rebif. The first biosimilars in MS will likely be versions of Teva's Copaxone (glatiranet acetate), though biosimilar Avonex already exists in Iran. Biogen is in a good position because of its rich MS pipeline, and by the time a biosimilar to Avonex hits the market, many patents will already be on Oral BG00012 or injectable Daclizumab and Pegylates Interferon Beta.

Large generic companies, such as Teva and Novartis will benefit from producing multiple biosimilars (such as Lovenox).

A smaller company, with only one product (H.P. ACTHar Gel), Questcor will largely be immune from biosimilars since Te mechanism of action of this product produced from pig pituitary glands is still incompletely understood (and the draft guidelines make it difficult to produce biosimilars in such a case).

3. Indian and Chinese companies have a lot to gain from these draft guidelines, and eventually they will dominate the market, just as they do to some extent in terms of oral generics -- however, the infamous Chinese heparin scare, may make many uneasy and the FDA granted itself a lot of discretion in the approval process of individual biosimilars.

- Dr. Daniel Kantor, MD
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Comments on EMA's guidelines for biosimiliar beta interferons

This is the first of two part series regarding biomilars and how they may affect MS (and other diagnoses) in both Europe and the Unites States.

After the EMA issued its draft guidance on biosmilars to beta interferons Dr. Kantor was interviewed by Jennifer C. Smith-Parker of BioPharm Insight -- Biogen, Merck, Bayer's MS drugs safe from EU biosimilars competition for several years due to tough requirements - experts, which was picked up by the Financial Times - Pharma majors’ multiple sclerosis drugs safe from EU competition for several years

In the report below, you will find Dr. Kantor's full responses (blue) to questions (green) raised by an analyst report (black):

Highlights:

· The requirements accept a single, one year trial with MRI primary endpoint in RRMS patients as basis for approval. Further, the results can be extrapolated to related conditions such as clinically isolated syndrome. This is a 'discount' vs. the new agent approval requirements (two trials whose length is two years with clinical efficacy as endpoints). However, the requirements are far from trivial.
I agree. The EMA could have required a non inferiority study with a clinical outcome, but instead they agreed to settle on an equivalency study with a radiologic outcome. The most accepted clinical outcome in MS trials is annualized relapse rate reduction, and you need two large Phase 3 trials that last for 2 years, but MRI studies can be shorter (this is more similar to phase 2 trials used in MS research).

- MRI results are clearly correlated with clinical efficacy, but are far from being a classical 'tight' bio-molecular marker (such as those that exist for already approved Insulin, hGH, EPO or Neupo). Thus there could be significant individual patient variability. EMA's suggested end point is "combined unique active lesions (CUA, defined as new gadolinium-enhancing T1-weighted lesions and new/enlarging T2-weighted lesions without double 170 counting)". However, it notes a baseline may need to be established and potentially a control group may be needed to calibrate the study. We expect that designing these trials will be difficult and they will need to be fairly large to deal with patient variability.

Recent trials, such as Teva's BRAVO study of oral Laquinimod for RRMS have highlighted potential barriers in matching for baseline MRI characteristics. Differences in the baseline characteristics may lead to unexpected disappointing outcomes. Theoretically an equivalence study could be negative, not just because the biosimilar may look worse than the original reference interferon, but also if it looks better than the reference interferon. If the EMA had allowed a non-inferiority study design, a biosimilar could unlikely but theoretically claim that it was superior to the reference interferon.

- Significant pharmacodynamic data and markers of immunogenicity (neutralizing antibodies) collection are required. Each difference between reference product and the biosimilar would need to be justified. The causes and effects of these differences are not always very clear. Again, this is a risk for approval.
- We note that the only company to develop a beta interferon biosimilar so far was Biopartners (Biferonex IF-beta), which failed to gain approval.
My questions: How large, specifically. do you think a control group should be? What beside the patient numbers makes the trial designs difficult and why?

The trial would not have to be as large as the > 1,000 subject phase 3 trials that we have become accustomed to because we are only looking at MRI changes and not primarily clinical factors, but the issue with both equivalency and non-inferiority studies is that there is a temptation to make these trials small because this would make it difficult to find a difference between the two groups, as opposed to a superiority trial, where you want the trial to be as large as you can afford (financially and time-wise) so that you are more likely to show a difference in the two groups. The EMA has tried to solve this problem a little by requiring both the reference interferon and the proposed biosimilar to be compared to placebo, and only if they both look better than placebo can the be compared to each other properly. While the proposed 4 months of placebo exposure is short, it does make it harder to convince patients and investigators to get involved. The EMA partially solves this by allowing the thirs comparison arm to be a lower lesser effective dose of the biosimilar rather than placebo, but it would be more difficult to show that the reference interferon and proposed biosimilar are superior to a lower (and potentially still effective) dose of the biosimilar.

The intricacies and subtleties inherent in an equivalency study make it more difficult to design well, and there isn't an established way of doing such a study in the MS world -- any sponsor considering this would be forging a relatively new scientific and statistical path.

· The commercialization of biosimilar beta interferon will be challenging. Our view is that while hospital products will be relatively easy to commercialize assuming the scientific data is strong, retail-type products will be tougher to commercialize for two reasons (i) Complex (dis)incentive structures in the channel and (ii) need to build a sales force and convince a broad group of physicians. In the MS there is particularly difficult challenge as physicians are risk averse as there is a material question of determining disease progression (i.e. it is tough for a physician to tell if a drug is working in his own patients).

My questions: Can you please explain disincentive structures? I don’t quite get that. Why is there a need to build a sales force for a biosimilar product here? Not sure I quite understand that. Also not sure why particularly challenging in the MS space; what does being risk adverse in this case and determining disease progression have to do w/ biosimilar product acceptance?

I think that the operative word is "complex;" it sounds like they are referring to the heavy involvement of Pharma in the MS world and the clear dissatisfaction that current interferon manufacturers would express to prescribers (in a number of subtle, and potentially, not so subtle ways). A biosimilar product is not the same product -- Nike and Reebok shoes are similar products, but they still need their own competing sales forces. Physicians have also been used to the brands of the reference interferons for almost two decades, and any new (biosimilar) interferons on the market may not be well recognized or understood by many prescribers. Unless the prescriber was forced by the insurance carrier to choose the biosimilar over the reference interferon, it is unclear why a prscriber would want to take the chance that the two are not really exactly the same.

In many other disease states, the patient and the doctor know whether a treatment is working for them. In MS disease modification, we are using the medications as insurance for the future -- taking the medication is supposed to prevent future relapses, not fix problems already present. This is one of the greatest difficulties in maintaining patient adherence to therapy -- if you don't know that you are feeling better from a treatment, you may not simply continue it because it may protect you in the future. When physicians treat hypertension, we know in real-time whether the blood pressure is lower and better controlled than it was before initiating treatment. When physicians treat MS, we can only opine retroactively whether the treatment was beneficial or not. Additionally, because of the highly individualized and variable course of MS, a patient may do well because they were "destined" to do well with or without a particular treatment, and converesely, some patients will worsen no matter which treatment (or no treatment) is chosen. This is why NeuroFunctional Enhancers (NFEs) are so empowering to our patients -- these are treatments that enhance the neurologic functioning of our patients in real-time, and patient either respond to them or they don't, but that response is noticed within the first 2 months of treatment (examples include Acorda's Ampyra and Avanir's Nuedexta).

· We think several products will be commercialized, but not as many as in the antibody field for three reasons: (i) These products are generally commercially smaller than most antibody products targeted in the first wave of biosimilars (and will get smaller as the new generation of MS products gain dominance); (ii) Beta interferon's require largely dedicated manufacturing equipment, having limited overlap with antibody manufacturing; (iii) As discussed above, trial risk is relatively high and will require relatively larger investment in marketing and sales. Interestingly, some of the biosimilar leaders (Novartis, Teva) have mixed incentive structures; they have innovative products in the market and do not necessarily want to see price attrition in the beta interferon category (although this may change for Teva).
My questions: What products in the MS field do you think will be commercialized? Have heard Rituxan from one doc already. Why do beta interferons require dedicated manufacturing equipment?
Rituxan will definitely NOT be commercialized -- Roche is moving forward in two phase 3 trials for RRMS (OPERA 1 and OPERA 2) on the fully humanized version, Ocrelizumab). New treatments closer to commercialization are BG12, Lemtrada and Teriflunomide. Manufacturing beta interferon is labor intensive because there are many steps:

1) Obtaining an interferon beta gene by extracting the gene coding for interferon beta from human fibroblast cells.
2) Modifying the gene
3) Making a recombinant DNA molecule
4) Adding the recombinant DNA molecule to a bacterium
5) Producing interferon beta-1b by bacterial fermentation6) Extracting interferon beta-1b from the ferment
7) Adding inactive ingredients

The machines to do all this are different than those used to make other biologics.

· The cross-read to Copaxone. We understand Copaxone was initially included in the scope of the beta interferon guidance and eventually excluded. Synthon's clinical trial of Copaxone and commentary from market participants suggest to us EMA requirements for Copaxone are similar to beta interferon, but the approval would be as a generic, not a biosimilar. We also understand some companies are challenging this guidance.

My question: Can you shed some light on why some companies are challenging this guidance? What significance, if any, is there for you that EMA is not considering Copaxone as a biosim but as a generic?

Synthon's protocol for their trial of GTR is more stringent EMA's draft guideline on similar biological medicinal products containing interferon beta because GTR is being compared to Copaxone for 24 months (instead of 12) and the placebo arm lasts 9 months (instead of 4).

Current manufacturers of Beta interferons will challenge the EMA's draft guidelines because it opens a route for biosimilars, and thus threatens their market, just as Teva opposes a route for biosimilar Glatiramer Acetate. The definition of a generic vs. a biosimilar will be meaningful to prescribers and patients, as genetics are often prejudiced as being not as good as the original branded products. On the other hand, the term "generic" is one that the Public is well aware of, and is sometimes equated with "the same but cheaper."


The second report in this series regarding biosimilars may be found here.


- Dr. Daniel Kantor, MD
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Letter of Appreciation: Gilenya clinical trial

We received this amazing note and we were given permission to share it for your benefit:

--

Hi Dr. Kantor,

I have been meaning to write you for a while and let you know what I am up to now.

I got into the Gilenya Guide Network and travel as a patient guide on behalf of Novartis and talk to people about my experience.

Basically, my "story" recounts how I had reached the end of my rope with other MS therapies and came to you as a new patient and got into the TRANSFORMS trial at your urging, and ends with what it has meant to me. The more I deliver this talk, it has become very clear to me just how HUGE a role you have played in the course of my MS, and thus my life.

If it hadn't been for you traveling around giving your MS Town Hall meetings, encouraging MSers with your self-advocacy message, and presenting us with all of the hope that research held for the future of MS, I may well have given up. I look back on that time as a period in my life that was lacking hope and full of despair.

So, from the bottom of my heart, I'd like to thank you for all that you have done and continue to do. Not just for me, but for all MS patients. Without your encouragement and dedication to education and research, I'm not sure where I would be today. I just know I owe the fact that I have not relapsed since April 07 to you.

Also, I am interested in becoming more of an MS activist. Novartis trained the patient speakers and since I attended that training and found my "voice" I no longer have such a terrible fear of public speaking and feel that I could go to Tallahassee or Washington even, and testify as an MS patient in whatever capacity is needed to either bring about changes in the law or increase funding for research. If you have any need for my assistance, please let me know. I'd even do webinars. Anything to raise awareness and/or effect change.

--

Thank you -- you make it all worth it!

- Dr. Daniel Kantor, MD

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

MSF Teleconference with Dr. Kantor on MS Treatment

MSF (MS Foundation) Teleconference/Webconference:

MS Treatments and Symptom Management
Daniel Kantor, M.D., Neurologist

Tuesday, March 13th, 2012
9:30 p.m. – 10:30 p.m. Eastern / 6:30 p.m. – 7:30 p.m. Pacific

To join, follow the instructions below:

1. Join the conference call:

Dial: 866-299-7945
Access Code: 9500667

2. To view the slide presentation during the audio conference, join the online session
http://www.sipbound.net/join?id=11932757&password=

Meeting ID: 1193-2757
Meeting Password: No password needed

Letter of Appreciation ... Doing Amazingly Well

With all the media concerns regarding Gilenya (Fingolimod), it is nice to see a success story (individual results vary):

AMAZING NOTE FROM FORMER RESEARCH "SUBJECT" (i.e. PERSON with MS)

Hi Dr. Kantor,

I have been meaning to write you for a while and let you know what I am up to now.

I got into the Gilenya Guide Network and travel as a patient guide on behalf of Novartis and talk to people about my experience.

Basically, my "story" recounts how I had reached the end of my rope with other MS therapies and came to you as a new patient and got into the TRANSFORMS trial at your urging, and ends with what it has meant to me. The more I deliver this talk, it has become very clear to me just how HUGE a role you have played in the course of my MS, and thus my life.

If it hadn't been for you traveling around giving your MS Town Hall meetings, encouraging MSers with your self-advocacy message, and presenting us with all of the hope that research held for the future of MS, I may well have given up. I look back on that time as a period in my life that was lacking hope and full of despair.

So, from the bottom of my heart, I'd like to thank you for all that you have done and continue to do. Not just for me, but for all MS patients. Without your encouragement and dedication to education and research, I'm not sure where I would be today. I just know I owe the fact that I have not relapsed since April 07 to you.

I don't know if you have considered it or not, but I think you'd be an awesome presenter for the Gilenya Guide Network. These meetings always have a neurologist who presents an FDA approved slideshow about Gilenya and then answers audience questions afterward. Your energetic and charismatic speaking style would really impact the audience, I'm sure.

Also, I am interested in becoming more of an MS activist. Novartis trained the patient speakers and since I attended that training and found my "voice" I no longer have such a terrible fear of public speaking and feel that I could go to Tallahassee or Washington even, and testify as an MS patient in whatever capacity is needed to either bring about changes in the law or increase funding for research. If you have any need for my assistance, please let me know. I'd even do webinars. Anything to raise awareness and/or effect change.

... Thank you for your update

- Dr. Daniel Kantor, MD

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

*** FSN Press Release: Florida legislature protects youth athletes ***

Media Advisory
For Immediate Release

Contact:

 Daniel 
Kantor, 
MD

March 8, 2012

Florida Society of Neurology (FSN) Applauds FL Legislature On Passing Concussion Bills




Gainesville, 
FL
 (March 8, 2012) 
–
 The Florida Society of Neurology (FSN) congratulates Representative "Doc" Renuart and Senator Flores on leading the charge to protect Florida's youth athletes through the passage of CS/HB 291.

Sports related concussion is a form of traumatic brain injury that can occur during any activity and to anybody. There has been recent media attention on professional athletes, and the Florida legislature has made a bipartisan unanimous decision to afford Florida's youth protection from potential brain injury.

According to Daniel Kantor, MD, President of the Florida Society of Neurology and a Director of the Seeing Stars Foundation, "the FSN is committed to continuing to work with the Florida High School Athletic Associate sports medicine advisory committee on ensuring the protection of brain health by establishing a subcommittee on sports-related concussion to oversee policies and educational efforts."

The FSN recently elected Frank Conidi, MD, DO, Executive Director and Founder of the Seeing Stars Foundation, to the FSN Board of Directors and appointed him to serve as the Advocacy/Legislation Committee Chairman. The mission of the Seeing Stars Foundation is to support research and education on sports related concussion and sports related neurological injuries.

According to Dr. Conidi, "neurologists are taking the lead in educating the public and other physicians on the importance of taking players out of the game when a concussion is suspected and of having an MD/DO with training in concussion diagnosis, evaluation and management only allow those players to return to play when deemed medically appropriate." The FSN and the Seeing Stars Foundation are offering educational opportunities for healthcare providers to receive additional training in sports-related concussions.

CS/HB 291 will now be sent to Governor Rick Scott for his signature, and mandates:

1. Education of athletic coaches, officials, administrators, and youth athletes and their parents or guardians on the nature and risk of concussions.
2. A low threshold for taking players out of the game when a concussion is suspected.
3. Return to play only after medical clearance,
4. Establishment of a sports medicine advisory committee within the Florida High School Athletics Association.

Last year the FHSAA set up a sports medicine advisory committee, which resulted in the FHSAA adopting policies and procedures mirroring the new legislation and mandated that only MDs/DOs can return a youth athlete to play after a concussion. The expanded sports medicine advisory committee will likely reconfirm these policies and procedures. In 2011, a neurologist, Hal Pineless, DO, President of the Florida Osteopathic Medical Association was appointed to the FHSAA sports medicine advisory committee. The FSN will continue to work with


For more information please contact:

Daniel Kantor, MD

fsneuro@gmail.com

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