BG 12 Problems?

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BG 12 Problems?

Postby HarryZ » Fri Jan 18, 2013 10:31 am

Has anyone heard rumblings about problems with Biogen's BG12 oral? Supposedly in the trials there are high infection rates with even some cases of PML. Have been unable to confirm this.

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Re: BG 12 Problems?

Postby CaliReader » Fri Jan 18, 2013 4:40 pm

Hi Harry,

I'm still new to MS and to this board, but I've looked very closely at this question.

The only thing I have found is the news about Teva's letter to the FDA requesting further safety testing of Biogen's BG12, based on possible kidney issues.
http://www.bloomberg.com/news/2013-01-1 ... views.html

I've looked at most of the academic articles I found on BG12 because I was seriously considering trying to take it on approval. I hate needles.
The most serious thing that concerns me is that the duration of fumaric ester treatment for psoriasis does not seem to extend beyond a year usually. So the decades of safety information from use for psoriasis in Germany on many thousands of patients are short term only and are not equivalent to long term MS use. I'm still thinking about taking it, but might wait a year or so, to see if problems emerge.

I don't know if you are familiar with the term 'FUD' in marketing and PR? It stands for Fear, Uncertainty, Doubt, and is part of the standard competitive technique of the people who make their living by shaping public opinion.
http://en.wikipedia.org/wiki/Fear,_unce ... _and_doubt

We represent a multi-billion dollar revenue stream to these companies. That fact represents my biggest temptation to just take nothing and deny them the profit from my disease. However, I'm so far resigning myself to being an informed and cynical consumer of both mainstream meds and alternative therapies.

But when companies are faced with a major shift in MS drug use, I'm not surprised that there are unsubstantiated rumors of very bad outcomes. If there really is PML from BG12, I would very much like to know.
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Re: BG 12 Problems?

Postby HarryZ » Fri Jan 18, 2013 5:26 pm

Hi CaliReader,

It's not surprising that the letter from Teva to the FDA was published by Bloomberg news. They have a bit of a history in reporting Biogen's actions.

I have said for many years that the MS world of medicine is a big financial game played out by about 4 different big pharma companies. The money they make off MS patients is HUGE and like you said, a slight shift in the market share can end up meaning millions and millions of dollars of either lost or gained revenue.

Biogen has one of the best marketing/sales departments going and they can spin information like nobody else. Before you make a final decision on using BG12, please become well informed.

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Re: BG 12 Problems?

Postby CureOrBust » Fri Jan 18, 2013 5:55 pm

I tried a search for PML and BG12 in Google. All I could find was references in post on other forums and where natalizumab / Tysabri are referred to in the same news article. ie no confirmation of any PML specifically for bg12 as far as I can see. It may just be people misreading online articles in haste; or just a well kept secret.
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Re: BG 12 Problems?

Postby cheerleader » Sat Jan 19, 2013 11:49 am

BG 12 FDA approval has been stalled- at least until the spring.
One concern which has been brought up by pharmaceutical industry specialist David Cavalla is that there is not a specific method of action on the immune system for this drug. It appears the drug is modulating the immune system somehow...but Biogen is not clear how. The Nrf 2 pathway activation thru glutathione depletion is the only known. And as Cure would tell you, you might as well use Curcumin (or Protandim) for that, and save some money.

Mechanism of action: I have heard it said that the development of compounds without a well-understood mechanistic target is ‘bad science’. There are many such compounds used as pharmaceuticals, so this may represent an extreme or even naive view. Various hypotheses have been advanced for DMF’s mechanism of action, including modulation of the intracellular redox system resulting in consequential effects on nuclear factor kappa B, TNF-alpha, interleukin (IL)-8 and IL-1b. From then, we see effects on anti-inflammatory cytokines such as IL-10 and IL-1RA; decreased expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin; stimulation of TH1 and down-regulation of TH2 T-cell subtypes; and induction of apoptosis in antigen-presenting cells and induction in anti-inflammatory stress protein heme oxygenase 1.

But no precise mechanistic target: so is this a deficiency in the regulatory package that Biogen-Idec will submit to the FDA; or if not, how will it address this question?

http://numedicus.co.uk/blog/

The Teva petition is really worth a read---- here it is online, in toto.
http://freepdfhosting.com/efaf2ebf45.pdf

Look specifically on pages 7-9, where it discusses the side effects of BG 12 in long-term animal studies...including adverse renal effects and proteinuria. (The only references to PML were made in terms of Tysabri) The problem in comparing BG 12 to fungiderm, is that fungiderm (the form of DMF approved for psoraisis) is only prescribed for short term use--like 6 months. We have no idea how long term oral use of this molecule will effect humans. And that's a problem-
For those on Facebook who want to learn more, I wrote up a pretty detailed note.
https://www.facebook.com/notes/ccsvi-in ... 4812867211
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Re: BG 12 Problems?

Postby NHE » Sat Jan 19, 2013 12:49 pm

Some component of the benefit in psoriasis could be due to simple immune suppression...
bg-12-dimethyl-fumarate-f52/topic20845.html#p198425

Reversible leucopenia, lymphopenia and transient eosinophilia are also frequently observed [2]. Leucopenia occurs in a quarter of patients [8,29]. A reduction in lymphocyte count occurs in around 70% of patients [6,8,25,29] and can exceed 50% in about 10% of patients [4]. The dose of Fumaderm® should be reduced if lymphocytes fall below 0.5x109/L or leucocytes fall below 3.0x109/L; if blood counts improve, treatment can continue at the reduced dose, but otherwise Fumaderm® should be stopped [9]. It has been reported that patients with lymphopenia are significantly more likely to show improvement in psoriasis than those whose lymphocyte count stays within the normal range [6,22,24].
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Re: BG 12 Problems?

Postby Loriyas » Sat Jan 19, 2013 1:10 pm

Keep in mind Teva has a lot to lose when BG 12 is approved.
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Re: BG 12 Problems?

Postby HarryZ » Sat Jan 19, 2013 2:28 pm

In particular,Biogen recently posted some troubling information about the safety and effectiveness of Panoplin (dimethyl fumarate) capsules, also known as BG-12, on a publicly accessible website.43 In addition to constituting unlawful, pre-approval promotion of an unapproved drug product, the website contained animal toxicology data suggesting that dimethyl fumarate ("DMF"), the active ingredient in BG-12, may carry potential risks for renal adverse events.


Now there's the Biogen I've come to know and distrust!!

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Re: BG 12 Problems?

Postby cheerleader » Sun Jan 20, 2013 11:26 am

Thanks for the now-defunct product name of BG-12, Panoplin, Harry.
That led me to the PML info, which is related to depletion of lymphocyte counts in Fumaderm usage. NHE is right about lymphopenia. This was in the footnotes of the TEVA letter I linked above, and is now being discussed on Cafe Pharma (a truly entertaining site!) The Panoplin site has been taken down.

43 Panoplin Website Screenshots (Exhibit 7) (accessed December 6, 2012). The website for Panoplin is active and publicly available at http ://warden.7te.net/index.html . Although it was revised in mid-December to refer to "Product X," it currently contains detailed product information about Panoplin as a "new" and "approved" oral MS medicine in direct contravention of FDA's pre-approval promotion restrictions.
44 Panoplin Website Screenshots (Exhibit 7).
45 Recent scientific evidence also suggests that DMF may be associated with PML and KS . In trials, BG-12 therapy resulted in substantial declines in white blood cell and lymphocyte counts, and grade 3 or higher lymphopenia (lymphocyte counts ofless than 0.5x 109 per liter) was seen in between 4% and 5% of patients in the BG-12 groups versus less than 1% in the placebo groups. Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis, New England Journal of Medicine, 367:12, pp. 1087-1097 (Sept. 20, 2012);
Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis, New England Journal of Medicine, 367:12, pp. 1098-1107 (Sept. 20, 2012). Although there were no reported cases of PML or KS in the pivotal clinical trials for BG-12, at least three cases of PML and one case of KS have been reported in patients treated with Fumaderm.

http://www.cafepharma.com/boards/showth ... ?p=4618846

From Timothy Vollmer's presentation on BG-12--page 44
Fumaderm: 3 PML cases, Karposi's Sarcoma-2 cases, and gastric cancer in rodents.
http://www.ucdenver.edu/academics/colle ... ollmer.pdf


Again, the issue may simply be that fumaderm is never used long-term. Usage goes from a couple of weeks, to a couple months, max. We just do not know what the consequences of long term use of this medication will be in people who already have a compromised blood brain barrier.
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Re: BG 12 Problems?

Postby HarryZ » Sun Jan 20, 2013 5:13 pm

Hi Cheer,

I rest my case :-)

Some people accuse me of having an agenda against Biogen. Not an agenda...I just don't like the company and after reading these recent posts, my opinion of them won't change any time soon.

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Re: BG 12 Problems?

Postby cheerleader » Mon Jan 21, 2013 11:37 am

Appears to be 4 cases of PML and Fumaderm---here's more from Dr. Giovannoni from Barts and the London MS blog--

"PML as a complication of BG-12 therapy is a potential risk that is currently undefined. The risk is likely to be very low and limited to patients with lymphopaenia. We will monitor your blood counts for lymphopaenia and if your counts drop too low we would obviously stop the drug."


http://multiple-sclerosis-research.blog ... rates.html

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Re: BG 12 Problems?

Postby marcstck » Mon Jan 21, 2013 9:16 pm

In regards to the mechanism of action of BG 12 being largely unknown, keep in mind that the mechanism of action of the interferon drugs, when used to treat MS, remains an unknown. They are thought to be immunomodulators, but is it merely coincidental that they are powerful antivirals as well? Given that human endogenous retroviruses are appearing to figure more and more prominently in the MS pathogenesis picture, antiviral action could very well explain some of the interferons limited effectiveness.

As for the effects of the long-term use of BG 12 being an unknown, the long-term use of all of the new generation MS drugs, starting with Tysabri, is a huge unknown. Typically, clinical trials run for about two years, followed by drug approval if the trials are deemed successful. The drugs are then marketed to patients who are expected to be on them indefinitely. Having said that, Tysabri has so improved the quality of life of many patients who take it that they are loathe to stop the drug even when they test positive for the JC virus. On MS Internet forums throughout the web, I see patients who go into panic mode when told they must stop their Tysabri treatments because the drug has had such a positive influence on their day-to-day existence.

Bottom line, MS is a dreadful disease, and in some cases it seems the evil unknown is better than the evil known…
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Re: BG 12 Problems?

Postby HarryZ » Tue Jan 22, 2013 7:53 am

Marc,

My biggest fear is that Biogen will introduce this drug the same way they handled Tysabri...damn the torpedoes, full speed ahead!! They are great at marketing and selling and line the pockets of the docs to entice them to prescribe their products. They also go the edge of ethics when advertising them and have been known to get their hands slapped by the FDA for false advertising. Unfortunately, it's all about the money for big pharma and collateral damage along the way is only a nuisance.

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Re: BG 12 Problems?

Postby cheerleader » Tue Jan 22, 2013 9:17 am

Hi Marc--
For some, agreed, the new drugs can provide a port in an horrific storm. The lack of an MOA in BG 12 issue was brought up by David Cavalla, a pharmaceutical reporter. I copy and paste. The PML issue is just surfacing.

My concern is that some neurologists, not all, do not disclose potential side effects of the newer drugs. Jeff was given the hard sale for tysabri by his neuro at his yearly appointment a couple years ago--even though he had no inflammation, no progression, no new lesions or disabilities and his gray matter looked normal on MRI. She said, "you are a man, you will progress--trust me, you want to do all you can." He told her his concerns with the drug, said he was doing well. Thanks, but no thanks. And she relented. The most recent appointment, he's still well, she told him to keep doing what he's doing. I hear from patients all over the internet who have been given this same story. Take this, to prevent future damage. And to those who do not know all the facts--taking the "most effective" drug, even though they're doing OK, seems like preventative medicine. We all want "the best." Whether it's the most prestigious neuro, highly regarded MS center, or effective drug. But it's not that simple. What happens if they become JC positive? The washout period for Tysabri (and potentially BG 12) can cause more inflammation and progression. The subdued immune system roars back to life. http://ms.about.com/b/2011/02/09/the-ty ... effect.htm I feel it's important for patients to be fully informed about all the options.
Especially now that Tysabri is applying for use as a first line medication.....this truly worries me. I share Harry's concern.
Tysabri use is currently limited to between 10 and 12 percent of treated MS patients, due to the risk of PML, and analysts said the hoped-for wider approval would improve uptake and send a positive signal to doctors.
Berenberg analysts said Tysabri's share of the MS market could increase to about 15 percent by 2015, representing sales of $2.9 billion, while today's share price for Elan implied peak sales of only some $2 billion.

http://www.reuters.com/article/2013/01/ ... J720130116
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Re: BG 12 Problems?

Postby smckee » Wed Feb 13, 2013 12:39 pm

This study compares BG12 to other Nrf2 activators in terms of oligodentrocyte protection from oxidative challenge:
http://registration.akm.ch/einsicht.php ... KEN_ID=900
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