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Posted by on May 19, 2009 in Ethics, FDA, Media, Neurology, Pharma

The NYT Misses in its Coverage of Iplex and ALS

The NYT Misses in its Coverage of Iplex and ALS


Last weekend’s NYT featured a lengthy story on ALS victim Joshua Thompson (“Fighting for a Last Chance at Life“) and his struggle to obtain access to the investigational drug Iplex (from Insmed) on a compassionate basis. Like most patient-centered articles in the mainstream press, the feature is heart breaking…and arguably irresponsible.

In what turns out to be really a very cloying piece, writer Amy Harmon takes the usual easy, uninformed (or perhaps just uninformative) road in pharma journalism by 1) stressing the ostensibly cruel indifference of corporate America and FDA bureaucracy; 2) downplaying the total absence of clinical data to support the use of Iplex in ALS; and 3) completely sidestepping the issue of poor medical policy as bullied into existence by an Internet-fueled public.

So here’s the…

Necessary Background

Iplex, a synthetic insulin-like growth factor (IGF-1) that is linked to a binding protein (IGFBP-3), was FDA approved in December 2005 for the treatment of growth failure in children with severe, primary IGF-1 deficiency. The drug received a priority review and was designated an orphan drug, because of the rarity of its indication. But Iplex was removed from the market in early 2007 after Insmed settled a patent dispute with Tercica and Genentech. These companies held the patent on a similar rival drug, Increlex, a synthetic IGF-1 without the binding protein. Increlex was FDA approved in August 2005 for the same rare condition.

In its defense, Insmed pleaded that Iplex should be made available and its development continued, given the drug’s other potential indications, including ALS and multiple sclerosis. Proponents also argued that the drug’s distinctive binding protein (in contradistinction to Increlex) facilitates entry of IGF-1 into the central nervous systema purely theoretical proposition. Bolstering Insmed’s argument was the fact that the Italian Ministry of Health had asked Insmed to make Iplex available to the country’s ALS patients, despite the fact that no clinical (or even published preclinical) data existed to support the drug’s efficacy or safety in the condition. Through several court rulings, Insmed then worked out a deal with Cephalon, the European patent owner of IGF-1, to provide Iplex to about 100 Italian citizens in an expanded access program (which the government paid for, to the tune of $100,000 USD per patient per year).

In the United States, some ALS patients had acquired Iplex off label before the drug was pulled. In online testimonials, these patients crowed about the drug’s benefitsthereby prompting individuals like Joshua Thompson and their families to invest tremendous hope, time, and effort in acquiring Iplex by whatever means necessary. Thompson even contemplated moving to Italy, until he discovered that Iplex was only available to Italian citizens.

Harmon chronicles the crusade of Joshua’s mother, Kathy, to get compassionate access to the unproven drug for her son. Perhaps most disturbing is Harmon’s unwitting example of the insidiousness of the online testimonial: Because of a single forum post maligning the effect of Increlex, when compared with Iplex, Kathy Thompson believed that only Iplex would help her son. 

IGF-1 Clinical Data Disappoint

Up until recently, results of well-controlled clinical studies of subcutaneous IGF-1 (Increlex) were mixed. In a double-blind, placebo-controlled, randomized trial of 266 North American ALS patients, IGF-1 significantly slowed the progression of functional impairment in an apparent dose-dependent fashion. However, a similarly designed European study (N = 183) showed no benefits with IGF-1 treatment in ALS. Then last year, results of a definitive, phase 3 trial (N = 330) revealed no difference in the primary or secondary outcomes between IGF-1- and placebo-treated ALS patients at 2 years.*

The negative clinical-trial results with IGF-1 in ALS apparently eased the way for compassionate access to Iplex in the United States, since Tercica and Genentech could not hold a competitive position in this therapeutic area. More important, safety data provided to the FDA by the Italian Ministry informed the agency’s decision to grant restricted access to Iplex. So in March of this year, the FDAbowing to the grass-roots demand for Iplex from Kathy Thompson and othersdecided to allow access to the drug under an IND application. This decision was made to the consternation of several ALS experts (for excellent and more detailed coverage of this story angle, see the May 4th issue of Neurology Today). The 2 methods by which American ALS patients could (or can) obtain Iplex: 1) a single-patient IND application to the FDA that had to be received by March 6, 2009,** and 2) a randomized clinical trial.

Through his single-patient IND, Joshua Thompson received his first dose of Iplex on March 25th. An NYT epilogue reveals that Joshua reported subjective improvement in his swallowing with treatment; however, on April 12th, he was hospitalized with pneumonia and placed on mechanical ventilation, where he evidently remains.

ALS = amyotrophic lateral sclerosis; IND = investigation new drug.

* A small, double-blind trial of 2 doses of intrathecal IGF-1 in Japan (N = 9) provided mixed, but largely disappointing, results.

** Harmon writes that it’s unclear who’s paying for the drug.

bmartin (1127 Posts)

A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on and Twitter.


  1. IGF1 and IPlex may not give the same results because of the binding molecule.

  2. The theoretical possibility that the binding molecule in Iplex confers greater efficacy than IGF-1 alone is addressed in the post. However, most important, there are no clinical data, as yet, to support the conjecture that Iplex should be more efficacious in ALS than IGF-1.

  3. Thanks for this post, Barbara — the story in the NYT left me wondering about the evidence base for Iplex therapy.
    I was struck by the similarities between the pleas of Joshua’s mother (for Iplex) and the claims of the Alternative/Natural/woo-based medicine crowd (for their pet cures). Both seem to be driven by anecdote; neither has a persuasive (or even credible) evidence base supporting the value of their favored therapy.
    My heart goes out to Joshua Thompson and his family. However, given the paucity of evidence, might they be just as likely to see a benefit from colon cleansing or acupuncture (or even sham acupuncture) as from Iplex?

  4. Joshua Thompson and anyone else suffering from the sh*t sandwich that is ALS deserve unbridled sympathy, and their desperation is understandable. However, to grant access to a drug for which there are no reliable, supportive data is bad policy and sets an unfortunate precedent.

  5. Geez, people will arugue for terminally ill people to be killed upon request, but God forbid we should let them try an experimental drug….

  6. Dr. Jack, no one would object to Joshua receiving Iplex or another experimental agent in a proper clinical trial setting — that’s how the benefits and risks of potential new therapies are evaluated.
    But giving an untested agent willy-nilly to anyone who asks for it is NOT a clinical trial. Such casual arrangements do not provide meaningful information about drug effects and do not enable informed decisions about whether the next patient requesting the drug may be helped or hurt by the therapy. Moreover, such loose arrangements for access to experimental agents undercut the ability of researchers to conduct the rigorous clinical trials that are absolutely necessary to properly explore the effects of experimental therapies.
    Iplex may or may not help Joshua but the way he’s gotten access to the drug may well hurt current and future ALS sufferers. This short-circuit in the research process will make it more difficult and time-consuming to properly evaluate Iplex and other potential therapies for ALS.

  7. Dr. Martin, Darjeeling,
    Your point of view was barely covered in the NYT piece (which was more news magazine show type “heart rending story” than real journalism).
    But I still wonder if your criticisms apply in this case.
    If I understand it correctly, in a classic clinical trial half the qualifying patients would be given the treatment under test and half would get a placebo to act as a control group.
    But in the case of ALS where as I understand it the ALSFRS score is considered a reliable measure of disease progression and many placebo studies have already been done (so the placebo effect should be known) allowing all the patients to have the drug and then monitoring their ALSFRS scores should give significant data regarding the effectiveness of the drug.
    If the FDA requires patients be enrolled in a program of monitoring, why not let more have access to the drug? (especially considering a separate placebo study is underway).

  8. Mitch wrote:
    “If I understand it correctly, in a classic clinical trial half the qualifying patients would be given the treatment under test and half would get a placebo to act as a control group.”
    That’s generally correct, unless there is more than 1 dosage of the investigational drug being studied. Then the new drug and placebo are randomized in a 2:1 fashion, for example. Also, an important point to stress is that treatments (active drug and placebo) should be assigned in a blinded fashion (to both patients and trial assessors). In addition, in any ALS trial, probably everyone should receive riluzole, given its proven survival benefits.
    Mitch wrote:
    “But in the case of ALS where as I understand it the ALSFRS score is considered a reliable measure of disease progression and many placebo studies have already been done (so the placebo effect should be known) allowing all the patients to have the drug and then monitoring their ALSFRS scores should give significant data regarding the effectiveness of the drug.”
    Endpoints, other than the ALSFRS score, are appropriate in an ALS trial. The most desirable outcome, of course, is enhanced survival. Because so many anticipated and unanticipated factors can contribute to the placebo effect (the uniformity of the study population, drug side effects, the direction of the wind…), the placebo effect can only be accommodated in the context of a single trial and should not be extrapolated from one trial to the next (although it is frequently done).
    Mitch wrote:
    “If the FDA requires patients be enrolled in a program of monitoring, why not let more have access to the drug? (especially considering a separate placebo study is underway).”
    Compassionate access (although it has its place) is generally unfair to those individuals who sacrifice their lives to advance legitimate clinical science. People who participate in clinical trials do so at the risk of being assigned to placebo (or, in the case of ALS, placebo + riluzole) for the ultimate knowledge of all. Consequently compassionate access discourages enrollment in well-controlled clinical trials–which is especially problematic when trying to advance the treatment of relatively rare diseases (meaning that the pool of trial enrollees is relatively small). It is also irresponsible to provide wider access to a drug for which they are no well-controlled safety or toxicity data in the ALS population. It is also possible that Iplex may worsen ALS symptoms or even hasten death. Noone knows–which is the point.

  9. A lot of conflicting information here. My question regards the selection of candidates for the study, their prognosis and how these variables interact in this disease. As a layman whose wife was recently diagnosed with ALS — symptoms observed over two years and diagnosis confirmed in January and reconfirmed in May — still confined to one arm — most recent EMG suggests further involvement/progression in other limbs but no symptoms observed –I perceive a value in early disease evaluation of this drug as once the nerves die, they will not be restored — the objective of IPLEX treatment would be to halt or impede the progression of this disease.
    Compassionate use as end term approaches will not reverse the disease.
    We have two medical opinions of Rilutek — one from a local ALS center that says it can prolong life by 18 months — the other; useless. Reading suggests 2-3 months!

  10. As someone with ALS I am very concerned at the attitude towards patient advocacy being expressed on this blog. It needs to be recognised that there is no cure for ALS. Rilozole has only been shown to increase life expectancy for 2 to 3 months. Given that it is also known to impact on your liver, many of us chose not to take it. If a medical practitioner is suggesting that it adds 18 months, then they should be struck off.
    The real issue for pALS is the extraordinary timeframes inn getting new drugs to trial. Firstly, the knowledgeable general public are vary wary of FDA approvals and secondly when it takes on average 2.5 to 3 years to get a trial even approved, it needs to be recognised that this is the period over which another 30,000 ALS patients die. I recognise the requirement for double blind placebo trials, however consider this:
    When I was first diagnosed in April 2008, my neurologist suggested that I go on Lithium. He had read the paper released by an Italian team in December 2007. I turned this down because I could not see any valid results, given the small cohort and limited mouse model results. A year later I mentioned lithium and he was now against it – solely because a group of his peers had come out against, not because he had actually researched it. In the mean time, a group of 86 ALS patients came together with support from the PatientsLikeMe site, to run a trial of there own in the absence of anything being established via the FDA. No DB/Placebo trial, simple a group of people takig Lithium that then provided FVC and FRS scores on a regular basis. Within 6 months this trial had shown categorically that Lithium was having little or no effect.
    This was a group of “patient advocates”. A group of intelligent individuals who simply got on and did something the system was incapable of doing for them.
    ALS has been around for over 150 years. No viable treatment has been found in all that time and certainly now cure is on the horizon. When the system finally allows people to make decisions for themselves, in order to take a chance at slowing progression, when they are otherwise told by their doctors that their only solution is to “go home and put there affairs in order”, then the system is finally listening.
    IPLEX has not been proven as a cure. There are however indications that it is having some positive benefits for some patients currently on it. Anything that may slow progress provides time for pALS to enjoy family, life and hopefully allow them to still be around when a treatment finally shows up. Denying us of this is, as previously mentioned, effectively denying us of life.