IPLEX seems to be taking an all too familiar trajectory in the ALS world. A whole hell of a lot of hype based on.....what exactly? Although I can't but be annoyed by the original sources of the hype, I firmly maintain that the fundamental cause of this sad phenomenon is the lack of real choices and promise for those with the most devestating disease. We all need to change that.

Speaking of which, isn't there something that we, i.e. the members of the ALSTDI Web-community, actually can do - except for donating money?
I bet that ALSTDI e.g. could get a lot of free-of-charge literature and information searches if the Web-community was provided with a couple of relevant questions or areas to cover in order to assist you.

And so where does it mention that a trial has been run and show no efficiency in ALS???......how convinient that many here choose to read what benefits their point of view, so much for carefully balanced and fact based commentry.

Let's hope the ALSTDI molecule dosen't follow a similar "too familiar trajectory in the ALS world".....or is this exempt from our regular train of thought and evaluation.

Wayne,
You and I have both read through enough threads to know exactly were ALS cures as a whole stand as of today, and we both know that even if something was found today the reality of getting access to it will not be tomorrow.
Now what pisses me off immensely (and this is not intended for just you Wayne) is the bias that can be shown towards one therapeutic all because of the origin of information.
Iplex has had strong theory and scientific backing, so much that even ALSTDI are interested in IGF-1's role, as we all know the hurdle was and is crossing the blood brain barrier. This is a drug that was initially released for infants and approved by the FDA, but hey let’s question if it’s safe for adults!! No trial has in the past and of yet, nor the future been planed, set up or destined for any form of ALS. So what if it failed in MMD it isn’t ALS so why are the ney sayers suddenly vindicated in telling us all “I told you so” is far beyond me. It is showing benefit in over 50% of the people taking it at the moment and you know what that's a lot more than anything that's been tested in a SOD1 mouse has ever shown. So get off the high horse and until hard facts are released, if and when someone has the guts to put it into a mouse and trial it then we/you can gloat. The worst thing about Iplex is the price and availability, cause if it were cheaper like Lithium and accessible like Lithium everyone would be charging to the pharmacy to get it, at least then we’d have some real facts that we could all relate to and just like Lithium end speculation to any therapeutic value, the thing has minimal side effect if any.
So many have suddenly pined the hope of a cure on this “molecule” all because it came from ALSTDI. Suddenly everyone has lost any reality in the fact that this molecule has just as much chance of proving to be off therapeutic value as a glass of water, but everyone seems content on believing that we’re all well on the way to the end of ALS all that is a problem is when.
Sure Iplex can and may be nothing but a waste of money, so too is Rilutek/zole and MND/ALS associations world wide as well as the FDA have this as the only treatment for ALS, and what success if any does it show? But no campaign rains supreme to end the sale of this product purely in the interests of PALS everywhere. Oh yeah how cheap is it?
I remember all the buzz when tp40 or whatever it was, was discovered and that this was to be the molecule that therapeutics needed to target if we were ever to see the end of ALS, what’s happened to that? Lets not even try to discus SOD1 which is what the mouse model or the benchmark for any drug/therapeutic is tested against, this only covers 5-10% of cases of ALS and yet it has the final say on what is of value or not!
Let’s get a grip on the facts people and so far we have none if any that are unbiased and undoubtedly accurate we have little if any info on this molecule for a start just a tease, sort of like the ones peddled by the stem cell operators in China/Mexico/Belize etc.

I am not sure who of us are pinning our hopes on the molecule; I have only seen the thirst for more information and the rational explanation of why more information will be forthcoming down the road.

Your comments have made me think, though. I do apply more credibility to ALSTDI than others. That trust may be misplaced, but I think not. Why? For one thing, it seems to me that ALSTDI is searching for a therapeutic for a disease, not looking for a disease to fit a therapeutic. That may be overly simplistic, but it strikes me as the proper ordering of things.

---

Scott-CT-dx 09/07

Hi Nemesis,
Great question – there is a whole spectrum of ways that folks can participate and accelerate the research towards effective drugs. These range from direct contributions, organizing fundraises such as events including golfing, music, etc to networking or connections to political figures and so on. Given the need, no effort is inconsequential and I can only encourage folks to contact our office and ask how to help: you will be connected with folks who can give more specifics. I can point out one particular route which is to become a TDI Ambassador – find out more at http://www.als.net/ambassador/default.asp


Specifically, on the research area – what folks do already on this forum is of relevance. I and colleagues monitor the discussion and may extract aspects for our discussions and debates. At this point there wouldn’t be any good mechanism in place for reference retrieval, however.

---

John McCarty, PhD
Director of Therapeutic Investigation
ALS Therapy Development Institute

Wayne,
The 50% are the Italian patients and the infor is easily accessed by anyone visiting the Insmed web site, but that's just made up stuf oh and if you have some spare time read below but thenagain this too is made up stuff passed on from one Iplex member to another, how dare I sugest your coments be the standard negative passed on from one "nay sayer" to another many Iplex and related thread full of those sort of comments though.....:


The Scientific and Empirical Foundations of IPLEX for ALS

ALS is a fatal, progressive neurodegenerative disorder that has a relentless progression from onset towards total paralysis; death is typically from respiratory failure, usually within 3-5 years from diagnosis. There has been no known treatment, cure or hope. The only FDA approved medication for ALS is Rilutek, for which the most generous studies suggest that it extends life by 90 days and at a cost of $1000 per month. Rilutek further causes liver damage and extreme fatigue besides being ineffective.

Research has long shown that Insulin-like growth factor (IGF) has the potential to be an effective treatment for ALS. Free IGF is neuroprotective and spurs axonal outgrowth in vitro, as evidenced by the following study:
http://www.nature.com/neuro/journal/v9/n11/abs/nn1789.html

The second link states “experiments with another type of neuron and with several different growth factors verified that axonal growth was stimulated only by IGF-1”.
http://www.eurekalert.org/pub_releases/2006-11/mgh-gfs110306.php

Another research trial states “Compared with the placebo, 0.1 mg/kg/day rhIGF-I significantly attenuated the progression of ALS.13 These studies merit emphasis that IGF-I is biologically and structurally distinct from ciliary neurotrophic factor and brain derived neurotrophic factor.13
http://jnnp.bmj.com/cgi/content/full/69/2/199

The following link posits that Free IGF is the only growth factor shown to be neuroprotective, stating “In this regard, the IGFs have been shown to be neurotrophic factors, i.e., they promote the survival and differentiation of neuronal cells, including sensory, sympathetic, and motor neurons (MNs). In fact, the IGFs are the only known growth factors that support both sensory and motor nerve regeneration in adult IGF-I, is involved in brain plasticity processes and it specifically modulates synaptic efficacy by regulating synapse formation, neurotransmitter release, and neuronal exicitability”.
http://edrv.endojournals.org/cgi/content/full/26/7/916

IGF-I prevents neuronal apoptosis –“The ability of IGF-I (and IGF-II) to promote neuronal survival is associated with the ability of these factors to prevent apoptosis, and IGF-I appears to be a potent agent for rescuing neurons from apoptosis. For example, IGF-I prevents N-methyl-D-aspartate (NMDA)- and nitric oxide-induced apoptosis in hippocampal and cortical neurons”.
http://edrv.endojournals.org/cgi/content/full/26/7/916

Apoptosis is widely recognized in ALS and neurodegeneration. The following is from the ALSA. “Cells that do not receive the proper supplies will die, through a step wise process called apoptosis. This is a normal physiologic phenomenon and in fact apoptosis is crucial to the normal development of the nervous system. But halting apoptosis when it is producing degenerative change in the nervous system is now a prime goal for researchers trying to design effective treatments for ALS as well as for other neurological disorders.”
http://www.alsa.org/research/article.cfm?id=821


However, free IGF1, known by their pharmaceutical names Myotrophin and Increlex, have difficulties in dosing, half life and inability to cross the blood brain barrier. Iplex, which is free IGF combined with binding protein IGF-3, one of six naturally occurring binding proteins, has been shown to cross the blood brain barrier.
http://www.ncbi.nlm.nih.gov/pubmed/17008777?dopt=AbstractPlus.

Free IGF does NOT freely cross the blood brain barrier. http://edrv.endojournals.org/cgi/content/full/26/7/916 (section IV)

Iplex is also shown to reduce muscle atrophy http://www.ebmonline.org/cgi/content/abstract/228/8/891

Iplex is also shown to have a greater half life than free IGF “The half-life of IGF-1 in the ternary complex is >12 hr. Proteolytic cleavage of IGFBP-3 and interaction of the ternary complex with proteoglycans have been shown to release IGF-1 from the ternary complex.” This table shows the significantly extended half life of Iplex over free IGF.
http://www.rxlist.com/cgi/generic/iplex_cp.htm


Table 1. Mean (±SD) Pharmacokinetic Parameters in Patients with Primary IGFD Treated with IPLEXTM 1 mg/kg (n= 4)
Cmax(ng/mL) Tmax(hr) AUC0-60(ng hr/mL) Half-life(hr)
IGF-1 133±19 11.3±6.2 3654±237 13.4±2.7
IGFBP-3 1574±401 19.5±9.0 62525±8352 54.1±31

Multiple studies have been done on alternate delivery methods of IGF to try to overcome the dosing, half life, and side effect profile of free IGF, including intrathecal injection. The following abstract shows that intrathecal delivery of IGF has a modest but significant benefit in ALS patients. http://www.ncbi.nlm.nih.gov/pubmed/16197815?dopt=AbstractPlus.

In addition, studies have been done using a viral vector delivery, again, showing benefit.
http://www.ncbi.nlm.nih.gov/pubmed/12907804?dopt=AbstractPlus .

This study acknowledges the difficulty of getting enough IGF in the body for a period long enough to establish effect.

Dr. Eva Feldman, prominent ALS researcher, recently stated in her article titled “Insulin Like Growth Factors in the Peripheral Nervous System” that “… Despite the positive results in animal models, these therapies have not translated into successful treatment for human patients. Lack of IGF-I efficacy is most often due to inadequate delivery of IGF-I. The IGFs are regulated by a family of IGFBPs that protect them from enzymatic degradation in the circulation and sequester IGF in tissue compartments. The function of the IGFBPs is beyond the scope of this brief summary but cannot be ignored when considering IGF therapy.”
endo.endojournals.org/cgi/rapidpdf/en.2008-1020v1.pdf

This is where the Iplex story truly begins. ALS research has long tried to overcome the obstacles that free IGF (found in Increlex and Myotrophin) present. Dosing, half life, and side effects provided barriers to efficacy. With the introduction of Iplex, it was found that these side effects were overcome. The addition of the natural binding protein allows for significantly higher dosing, passes the blood brain barrier, and has a markedly increased half life. Iplex also has a significantly reduced side effect profile, and is delivered by once daily injection, rather than twice daily.

Iplex (mecasermin rinfabate) was originally FDA approved for severe short stature due to Primary IGF Deficiency (IGFD), and has been through varied stages of clinical testing for multiple other indications, including premature birth retinopathy , HARS, Noonan Syndrome, Myotonic Muscular Dystrophy, insulin resistance, Lephrechaunism and Laron Syndrome. The drug is safe and well tolerated, even in premature infants.

Upon the release of Iplex in November 2006, it was shortly thereafter off-label prescribed for twelve ALS patients in the US. Of these, eight were carefully monitored during the period of their Iplex usage between January – March 2007. The results were remarkable for these patients. Careful tracking and analysis confirmed that each of them experienced remarkable gains, in a short period of time, in multiple areas of function. Patients were able to change their dietary regimen from pureed foods only at the onset of Iplex usage to normal adult meals after a short period of therapy (as little as 5-7 days). All patients reported gains in multiple other areas of function, including but not limited to, improvement in weight gain, respiration capacity, hand and foot motor function, minimized spasticity and rigidity and reduction of untoward fasciculations. The multiplicities of these functional improvements suggest relief in both areas of upper and lower motor dysfunction. Because of the rapidity of the improvement onset, it is possible that patients benefited from both placebo effect and immediate neuronal reinnervation. After Iplex was summarily withdrawn from US and other market distribution in March 2007, and the then-existing supply of the pharmaceutical was exhausted, all patients shortly thereafter (usually within 3 -4 weeks) returned to their pre-Iplex condition.

Ben Byer, ALS patient and director of the documentary film “Indestructible”, best summarized the Iplex effect: “By removing IPLEX Genentech has monopolized the market on one of the most destitute, devastated and hopeless patient populations in the world with a drug that by my estimation is like trying to get drunk on cough syrup when there's a case of bourbon locked in the closet." Read the entire article at:
http://indestructiblefilm.com/blog/?m=200711

The Italian Ministry of Health, after successful litigation by an ALS patient in Italy, was court-mandated to provide IGF-1 to that patient and others so requesting IGF-1 to treat them. The only company to respond and comply with the MOH requests was Insmed, with their product Iplex. By January 2007 30 Italian patients had begun using Iplex under condition of a closely conducted observation by a local neurologist, rather than as a clinical test study. This became known as an expanded access program, since growing to more than 100 patients supervised by 22 treating physicians in less than 18 months. According to Insmed, no patients have dropped out of the expanded access program for safety or side-effect issues. Italian ALS patients have reported stabilization of progression, either at least significantly slowing or completely stopping progression. In some cases, significant improvement has also been reported. The following links provide patient, medical supervisor and Ministry of Health documentation of Iplex results (all articles following are in Italian):

This article is about Carlo Bruno, ALS patient who initiated the legal action against the Ministry of Health.
http://www.giornalettismo.com/archives/927/malattie-dimenticate-la-guerra-di-carlo-e-la-sla/

Regional councilperson Giancarlo D' Anna reports improvements in symptoms of patients with ALS taking Iplex in this article. http://www.cami74.com/modules.php?name=News&file=article&sid=15781

This patient reports no further progression of ALS for a one year period since beginning use of Iplex
http://www.xs4all.nl/~surg3on/INSM/20080302_ALS_EAP_testimonial.pdf

This legal article states that Iplex significantly improves patients with ALS lives
http://www.studiolegalelaw.it/new.asp?id=2077


This article quotes the former head of Ministry of Health as saying that Iplex was the first effective known treatment for ALS. http://www.sangiovannirotondonet.it/content/view/970/44/

This article from the Italian ALS association states that Iplex was the first drug to meaningfully slow down progression, and improve patient quality of life.
http://www.monzapiu.it/news/entry.php?id=93&w=cnd_news

Wayne,
The ones that have passed away were from complications not related to ALS, of course this would not be deemed a acceptable reply for you but hey.
I have a letter from one of the treationg Dr's who is part of the team who states these figures you, I will dig it up and post it soon, no I'm not stalling to fabricate as I'm sure I will be acused of LOL. And yes I do realise that the whole Italian thing is not a legitamate trial with double blind placebo yadayada...etc however all this has been discused in detailed argued documented questioned etc etc in the passed on other threads in this foum so we're just reliving everything again.
Thanks for adding critique to the scientific reasoning for Iplex....oh sorry no you didn't comment on that LOL

Is it your opinion that the answer to ALS will be found in a pill Wayne?

I just saw a TV news special on a new heart stemcell clinical procedure that shows promise of repairing damaged sections of the heart following a heart attack.

jomoco

My guess is that much of the positive response to the recently announced ALSTDI molecule on this forum has to do with confidence in the scientific methodologies used by TDI. Many of us have concluded that TDI is not going to make any positive comments about any potential treatment until very, very rigorous testing has been carried out. Caution has always been the watchword.