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Al

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IPLEX and the Telephone Game: The difficulty in separating myth from reality on the internet

First Published on: 08 January 2009

Many of us remember 'the telephone game'. In this, a short story is started and then whispered to a second person, who then whispers it to a third and so on down the line. The fun comes in hearing the last person in the chain relate the story out loud to the group. Inevitably, the story changes as it is passed on, sometimes dramatically. There is a similar phenomenon occurring recently on the internet related to treatments for amyotrophic lateral sclerosis (ALS), although the possible implications are anything but funny. An example is found in IPLEX.

IPLEX, or mecasermin rinfabate, is Insmed Incorporated's complex of recombinant human insulin-like growth factor-I (rhIGF-I) and its predominant binding protein IGFBP-3 (rhIGFBP-3). It is effective for treating children with growth failure due to primary IGF-1 deficiency 1 and is approved for this use in the United States. It is not approved for any other uses at this time. According to Insmed's website 2, it is under phase II study for myotonic dystrophy and there are 'early stage research programs' investigating retinopathy of prematurity (ROP) and HIV-associated adipose redistribution syndrome (HARS). There is no mention on Insmed's website of any trials being conducted in ALS, nor are we aware of any. Theoretically, it could be useful for ALS. Its main ingredient, IGF-1, has a history of being tried in three large randomized, double-blind, placebo-controlled trials 3-5. One of these trials 3 showed a statistically significant slowing in ALS progression relative to placebo (although the clinical significance of this small effect is debatable); the other two showed no clinical benefit. The addition of the binding protein may be able to enhance the bioavailability of IGF-1, leading to greater potency 1.

Since 2006, IPLEX has been tried by a small number of patients with ALS (PALS). Unfortunately, few objective data on their experience are available at this time. One blogger with ALS reported on his website that he briefly took IPLEX and noted the following: “Within days I experienced rapid improvements in walking, speaking, appetite, swallowing and - critically - breathing. It felt like my body was under a seismic shift and IPLEX was jolting the foundation of the disease. After trying more than 30 therapies over five years, I have a pretty good sense when something doesn't work. This was different…finding IPLEX was like the Allies liberating Auschwitz” 6. No objective confirmation of these symptomatic improvements was provided. Some Italian PALS using their own anecdotes successfully petitioned the courts for the drug. As a result the Italian Government agreed to pay Insmed to supply IPLEX to a certain number of Italian PALS. This petition initially relied heavily on the subjective report of benefit from one patient who has been hospitalized in different Italian neurological institutions but who is not uniformly recognized as affected by ALS 7. The Italian ALS neurological community reacted with appropriate concern. In November 2006, four Italian ALS experts, the Italian ALS Association (AISLA), and the Italian Medicine Agency (AIFA), after carefully evaluating the scant available pre-clinical and clinical data, recommended no further prescription of IPLEX for Italian PALS until those already in treatment could be examined for any side- effects or potential benefits 8-10. The same groups, joined by two other distinguished ALS neurologists in 2007 (Chi and Mora), suggested a double-blind clinical trial to settle the issue, fully aware of the potential consequences of the Italian experience on PALS both in Europe and North America. Funds for the trial were not available at that time. In the meantime, Insmed collected data from PALS in Italy treated with IPLEX, and preliminary results have been recently circulated inside AIFA, the ALS experts of the Italian Commission, and AISLA. As of October 2008 the total number of Italian PALS treated with IPLEX was 34: 13 on a dose of 0.5 mg/kg/day rhIGFBP-3and 21 on a dose of 1.0 mg/kg/day rhIGFBP-3. These uncontrolled data have not yet been officially released.

In March 2007, Insmed was forced to stop selling IPLEX for treatment of children with short stature as part of a settlement of patent infringement litigation with Tercica Inc. and Genentech Inc. The settlement allowed Insmed to develop, manufacture, and sell Iplex for myotonic muscular dystrophy (MMD), and HIV-associated adipose redistribution syndrome (HARS), subject to opt-in rights and royalty provisions for Tercica and Genentech 11. There was apparently no clear mention of ALS development in the original settlement; however, the three companies involved recently signed a letter of intent in which they consented to amend this original settlement to permit Insmed to supply IPLEX if indicated for ALS 12.

Despite the lack of good data, and the legal issues, the Italian experience appears to have generated an unusual amount of interest in IPLEX among PALS across the world. Online chat rooms have had lengthy discussion threads about it 7, 13. We have received numerous emails from PALS we care for and also from anonymous sources about it. Letters and petitions are being circulated online in an attempt to influence policymakers to make the drug more widely available to PALS outside Italy. There has even been a small march on Washington D.C. to support this attempt. It is interesting to monitor these sources to see how the IPLEX story is evolving. On one website, for example, several bloggers claim to have spoken to Italian neurologists and/or PALS in Italy and/or the lawyers of said neurologists or PALS, and that 50% of Italian PALS are apparently improving on IPLEX. When questioned about their specific sources, these bloggers claim they are unable to reveal them, lest the source be penalized and have to give up their IPLEX 13. One open letter on the internet, addressed to DePaul University School of Law states “With the arrival of Iplex, a drug, which was launched in the second quarter of 2006, there followed a number of very respectable studies (across the country/world) which went on to confirm efficacy in slowing down progression in ALS. As these very encouraging research results/data were being released to the public, PALS across the world were given reason for hope” 14. An online petition states “IPLEX was originally intended for the treatment of children suffering from hormonal growth problems but also offered great benefit to people suffering from ALS (a dreadful, terminal, neurodegenerative disease to which no cure has been found so far), showing improvements in their conditions. We, ALS patients from the United States of America and from European countries such as Sweden and Germany, demand equal access to Iplex, the only medication that has shown benefit so far” 15. Thus, we see the old telephone game in action: the IPLEX story starts with a few poorly substantiated case reports and by the time it is done we have “a number of respectable studies” showing efficacy for this, “the only medication that has shown benefit thus far”.

This trail of progressive misinformation would be bad enough if it was limited to IPLEX, but it is not. It is a growing problem on the internet. Before the recent IPLEX furor there was another surrounding lithium. A small but well-documented case series showed potential slowing of ALS progression on lithium 16. This was followed by a rash of unsubstantiated reports of dramatic improvement on it, including a widely viewed video of a PALS who reportedly regained the ability to run and ride his bicycle on it 17. Not surprisingly, many PALS wanted to try lithium. Those who wanted to experiment on themselves found physicians to prescribe it, and even found an online forum for entering their data 18. Now these lithium 'data' (none of which are validated or controlled) have been analyzed and there is reportedly no obvious beneficial effect, which has prompted calls to cease further study of lithium 19. Clearly, this type of misinformation (pro or con) could negatively influence enrollment in ongoing and future clinical trials in ALS and slow the development of effective treatments for ALS 20. It could also lead erroneously to moving a less-promising drug to the front of our current pipeline, or a more promising one to the rear.

What then can we, as ALS clinicians and scientists, do about all this? Specifically for IPLEX, we can urge Insmed to release its preclinical and early clinical data related to ALS. We could accomplish this via a letter on behalf of the World Federation o f Neurology Research Group on ALS (WFN/ALS), the ALS Research Group (ALSRG), or the European ALS Consortium (EALSC). Analysis of this could help us determine whether IPLEX warrants further study in PALS, and where it ranks in our current pipeline. For the larger problem this story illustrates, the problem separating myth from reality on the internet, there is some good news: available evidence suggests that most patients have tremendous respect for the opinion of their treating physician and health care providers 21. The bad news is that less than half the PALS in some countries appear to obtain care in dedicated ALS clinics 20. We need to do a better job of distributing information to PALS on the many benefits of attending specialized ALS clinics, on the many benefits of participating in the research studies offered there, and on the dangers of self-experimentation. We should refrain from off-label prescribing of unproven therapies. Most importantly, we need to educate PALS on how to distinguish myth from reality as it applies to the complex world of clinical research. Along these lines, we can make ourselves available online to PALS who attend our clinics so they can run their interests and concerns by us before embarking on a course of futile demonstrations or self-experimentation. The telephone game would not work if the story was repeated aloud each time, then corrected before it was passed on.

"Hope is the companion of power, and mother of success; for who so hopes strongly has within him the gift of miracles." Samuel Smiles
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Al

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The above article was copied from this weeks ALS Independence Newsletter. A bit long but well worth the time spent.

AL.
 

stmbt

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I had previously read this article when it was first published. I have personally used Iplex and experienced slight improvement in a short period of time. Each PALS is affected differently and so may exxperience different reactions to different drugs. Bedlack, one of the authors of the piece, publicly denounced the patient-led lithium trial in May in DC. We, as PALS, have nothing to lose by trying various treatments that we have thoroughly researched. The medical community has absolutely nothing to offer after more than 100 years. And yet, they feel it necessary to continually undermine everything that PALS present to them. Besides huge egos, I believe that money is behind their negativity.
 

shelly2612

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Are you still using IPLEX?

you stated you had used IPLEX, my question is: Are you still using IPLEX and is it helping you.
 

stmbt

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No, I am not. The patent infringement lawsuit between Insmed/Genentech/Tercica rendered Iplex unavailable to anyone. The suit was resolved in Nov 2008 and I am actively pursuing Iplex. However, the negative influence of Bedlack is impeding the pursuit.
 

clewbcg

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PALS Starting on Iplex Monday

My husband has been able to get iplex through a doctor and he is starting on it Monday. I'm wondering what kind of improvement did those who have taken it see? Also, any side effects? I am very wary of this iplex thing. It seems like a replay of the lithium situation which my pals also did. We saw no improvment at all-more like an increase in symptons. Anyone out there on iplex now?
 

hopingforcure

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your husband is actually the first one I have seen start Iplex since the FDA release. I have not heard people in Europe say about a lot of symptoms, children with failure to thrive ar e treated with this medicince, so hopefully that mean's good thngs as far as symptoms.'
I am hoping you will keep us posted on a regular basisi with your husband's results. I hope it is better than all the previous medicines. My neuro was not to excited about it. But maybe we will et a MIRACLE , we can hope. I heard it is 100,000 a year and not covered by insurance, so that is really going to keep treatment limited. GOOD LUCk:razz:
 

clewbcg

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my husband is getting it for free (except for a small processing fee). he says that the compassionate use protocol calls for it to be free. he filed his paperwork in January and got in before the March deadline through the proactive work of his respiratory dr. he says this iplex drug has a protein bound to it that makes it different from the basic human growth hormone tested on als before. our neuro is indifferent to it, but didn't discourage him from doing it through this other dr. he is not part of a trial and has pretty advanced symptoms-can't use his hands or arms hardly at all, speech and swallowing bad, on a bipap, falls alot, lost 30 lbs since last march etc. we just met about getting a feeding tube installed, but he won't do it-says he'll just drink 6 ensures a day, but he chokes and spits it out almost every time he tries to drink it. we are getting an electric wheelchair this month. I'll keep everyone posted on this thread about the iplex.
 

Zaphoon

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Brilliant article, Al! Thanks for taking the time to post it.

Zaphoon
 

clewbcg

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Update on Iplex

My husband has been on iplex for several weeks now, and I see no improvement. If anything is noticeable-he has gotten worse. Sorry, but wanted to let people know.
 

rocmg

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clew... i'm very sad to hear this. i was hoping that Iplex would prove the doctors and researchers wrong...
 

hopingforcure

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So sorry your hubby has seen any improvement thus far. I hope that it changes, but know that the members on this forum appreciate your honesty, and that you are keeping us posted.
 

strikeout

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My husband was curious if those on iplex are given any physical therapy along with the drug.
 

clewbcg

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My pals isn't getting any physical therapy associated with taking iplex. He does still work with a yoga instructor and a physical therapist that he started with before the iplex. What kind of physical therapy do you mean? Is there some that he should be doing with the iplex? His neuro isn't a part of this-just a pulmonary doctor who is also a friend, and he didn't mention any therapy. Hope this answers your question.
 

SteveS

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We had a discussion with our neuro yesterday at the GF Strong ALS clinic in Vancouver and she explained the hype around IPLEX for us. From what I took away from this conversation is most of the hoopla surrounding this medication is coming from the manufacturer themselves and that it doesn't look like anything will come from it. A clinical trial will have to be done before they start looking at it more seriously.
 
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