The demise of Combidex / Sinerem


For several years a company initially called Advanced Magnetics (and later known as AMAG Pharma), with its partners, spent a good deal of money developing and seeking approval of a product called ferumoxtran-10.

Ferumoxtran-10 was an imaging agent that, when used in combination with magnetic resonance imaging (MRI), appeared to be able to make visible, with considerable accuracy, the presence of cancer-containing lymph nodes in patients with progressive prostate cancer. In Europe the brand name from feromoxtran-10 was Sinerem; in the USA it has long been known as Combidex.

Back in June last year, we had commented on a then-recently published study that seemed to throw some light on why Combidex (although approved in some European countries) had never succeeded in gaining approval in the USA.

The precise situation was as follows:

  •  In June 2000 the U. S. Food and Drug Administration (FDA) issued an approvable letter  for Combidex requesting additional information.
  • Advanced Magnetics submitted a complete response to the approvable letter; this was accepted by the FDA, and an Oncology Drugs Advisory Committee (ODAC) hearing was held on March 3, 2005.
  • In Europe, a product dossier (the European equivalent of a NDA) was submitted to the European Medicines Evaluations Agency (EMEA) in December 1999.

Ferumoxtran-10 was subsequently approved for clinical use in some European countries. In late 2003 a paper by Harisinghani et al. in the New England Journal of Medicine offered extraordinary images of the way in which ferumoxtran-10 could demonstrate the presence of positive lymph nodes in patients with prostate cancer. Additional, detailed information about ferumoxtran-10 and its clinical use from 2004 is available on the web site of the Prostate Cancer Research Institute. However, ODAC voted 15 to 4 not to recommend approval of the proposed indication for this drug in the USA, stating that there were insufficient clinical data to support a broad indication for use of ferumoxtran-10 to differentiate metastatic from non-metastatic lymph nodes across all cancer types.

For many years there have been small numbers of patients who would travel to the Netherlands to get their lymph nodes checked using ferumoxtran-10. However, the maufacturer terminated production of the product several years ago. In an e-mail to Chuck Maack just recently, Prof. Jelle Jelle Barentsz of the Department of Radiology at the University of Nijmegen in Holland apparently wrote:

Yes I confirm. There is no contrast anymore anywhere in the world, because AMAG Pharma decided to stop the production 5 years ago. Combidex MRI stops next week on April 1st.

I am working on solutions.

As we wrote in our prior article, the development of a “second generation” imaging agent based on the science used to develop fermoxtran-10 would seem to be a promising opportunity. Ferumoxtran-10 seems to have had some relatively small underlying flaws, and in the USA the manufacturer may have been unwilling or unable to focus product development and approval on a limited indication that might well have been approvable.

We desperately need better tests that can be used to accurately detect the presence of prostate cancer once it has escaped from the prostate into other organs. It would seem all too sad if the research on ferumoxtran-10 cannot be used as the basis for another attempt to develop a a new imaging agent with a comparable safety profile and a slightly better effectiveness profile.

35 Responses

  1. Some of the top medical oncologists in the United States specializing specifically in research and treatment of prostate cancer have supported the importance of Sinerem/Combidex imaging by recommending to patients with suspected prostate cancer migration to lymph nodes to travel to the Netherlands for this important imaging. Patients returning have all heralded the importance of this imaging as well as the excellent care by Dr. Jelle Barentsz and his staff.

    In not having Combidex approval in the U.S., our country’s health system has been missing an excellent method to distinctly identify and pin-point lymph node involvement of prostate cancer.

    What is of additional significance is the importance of this imaging for several other medical issues. As noted in a report by the Life Extension Foundation (LEF), “the discovery of the remarkable properties of ultra-microscopic iron particles, and their appeal to the inflammation-seeking macrophages, has opened new vistas for making functional diagnoses — diagnoses that show physicians not only the structures that comprise our bodies, but also their activities at an extraordinarily detailed level. Combidex®, the commercially produced MRI contrast-enhancing agent that contains these space-age particles, has proven its effectiveness and safety in numerous studies. The ability of oncologists to find and react to metastatic lesions previously too small or too isolated for detection will change the roadmap of cancer therapy, while neurologists and cardiologists can look forward to new ways of visualizing the destructive inflammatory changes that accompany cardiovascular disease, stroke, and other chronic conditions. There is still work to be done to achieve the widespread recognition that Combidex® deserves—the work of devoted clinician-researchers such as Dr. Jelle Barentsz is sure to achieve this in the near future.”

    As a prostate cancer patient, advocate, and mentor, I would certainly encourage AMAG Pharma, the manufacturer of the contrast agent for Sinerem/Combidex, to continue manufacture of this important agent to continue the important inroads Sinerem/Combidex has made in MRI imaging.

    Charles (Chuck) Maack/Prostate Cancer Advocate/Mentor

  2. Great follow up by Mr. Maack. I too, would like to strongly support AMAG Pharm to continue to manufacture Combidex. The battle with cancer is difficult enough without 1 step forward and 10 steps back.

  3. I am a prostate cancer patient who went to the Netherlands for a Combidex scan by Dr. Jelle Barentsz. I strongly second Chuck Maack’s comments and Dr. Barentsz’s efforts to continue the Combidex program.

  4. Mr. Maack’s remarks are very appropriate and I am sure represent the feelings of cancer patients like myself who have experienced the benefits of the Combidex MRI.

    I have had prostate cancer for 18 years, with the initial treatment being a radical prostatectomy. Failure occurred within 15 months and since that time I have had full radiation of the prostate bed, participated in a vaccine clinical trial, received hormone therapy, received injections repeatedly to bolster my immunity, been on diets, and continually taken both prescription medicines and alternatives to control the growth of my metastatic disease. I underwent a Combidex (Sinerem) MRI under the direction of Dr. Barentsz in August, 2009 which revealed a metastatic lymph node which I subsequently had radiated. The result appears to have been successful in halting the metastasis. I now firmly believe that the Combidex MRI would have been very useful in combating my disease if it had been available many years ago.

  5. I visited Nijmegen UMC St Radbout as a “PSA recurrence” patient after undergoing HIFU treatment in Japan. I was going to have “whole body” MRI + MRL + local “functional” MRI. Since Combidex is no longer available I settled on the other two options to my total satisfaction.

    I cannot understand why we are not allowed to use latest technology. Prof. Dr. Barentsz’s commitment and passion to this cause is to be recommended

  6. This is a political problem in the U.S. Obama care will exacerbate it. Is there any hope for the re-establishment of ferumoxtran-10 soon in Europe?

  7. Respectfully, this is not a political problem at all. It was a commercial problem. The manufacturer was unable to make sufficient revenue from the use of ferumoxtran-10 in Europe, and was unable or unwilling to conduct the trials necessary to gain approval of ferumoxtran-10 in the USA, where they might have been able to generate sufficient revenue to maintain production. I think it is highly unlikely that we will see commercial availability of ferumoxtran-10 either in Europe or in the USA unless someone is willing to take on the challenge once the current patent on the product elapses.

  8. Do you know when the patent runs out?

  9. Nope. Haven’t got a clue, but it may not be that far away based on the time that was spent trying to get it to market and approved.

  10. Dr. Myers gave me hope last week that an alternative may be forthcoming by the end of the year. He thinks that I have a real chance at being permanently cured by this scan after 13 years of everything I could throw at it. I never expected to have another shot at a cure.

  11. Douglas: You have “lost” me. The Combidex test was simply a way to scan for positive lymph nodes. It is not a treatment for prostate cancer, so I don’t understand how Dr. Myers could have intended to suggest that it had any curative capability.

  12. It’s the key to the localized follow up treatment by surgery or radiation of positive lymph nodes for an indolent form of prostate cancer which has not metastasized but has a low doubling time during off cycles of IHT. Quite a few men have been permanently cured by the identification of the locality of such cancers and the treatment of those locations.

  13. Douglas:

    Anyone with positive lymph nodes most certainly does not have “indolent” disease. It may be slow-growing, but it ain’t indolent! And there is vast variation in the rate of growth of non-indolent cancer that has already escaped from the prostate. That rate of growth of the cancer depends on all sorts of factors — from the strength of the patient’s immune system to the degree of hormone-sensitivity of the cancer cells.

    Is it theoretically possible that someone who has a couple of positive lymph nodes removed can be cured? Yes. Of course it is. It is also possible that such patients will recur 3 months later because they also have micrometastases that are invisible to any form of scan (Combidex included). Having said that, if the Combidex test were to suddenly become available again, and you can afford to fly to the Netherlands to have the test, by all means try it, but please remember that no test is 100% accurate, and the Combidex test may well not show other micrometastases that could easily be present.

  14. It can be fast growing and also indolent. If Combidex had not faced the political, and thus economic barriers that prevented it from development, it would certainly be something that I would try.

  15. Is there any updated information about when Combidex scanning will begin again?

  16. We are not aware of any plans to re-start manufacture of ferumoxtran-10.

  17. The following was posted on the ACOR Prostate Problems Mailing List on July 16. It is a message from Prof. Jelle Barentsz to selected patients and others:

    Dear Patients and Colleagues,

    With this letter I would like to give you an update on the situation of Combidex/Sinerem.

    We had a good meeting in April at AMAG headquarters. Below you will see the meeting through the eyes of John Shearron, a patient who was with me having the Combidex MR-exam in the past.

    Patients perspective of AMAG meeting by John Shearron:

    AMAG pharma was a cooperative, respectful and delightful host. Their entire team participated in asking pointed and well thought out questions. While the loss of FDA approval for Combidex was a difficult and painful time for AMAG, to their credit, it didn’t stop them from seeing the potential use of ferumoxytol (Feraheme) as an imaging agent. This agent is approved for therapeutic use only. It can be given to patients with anemia in chronic kidney diseases (note from J.B.). Much of their success in getting Feraheme approved was due to their collaboration with the National Kidney Foundation. It was very clear that from the CEO, Brian Pereira, on down, AMAG has seen the power of the advocacy groups in educating the FDA.

    The comments of Dr. Faina Shtern of AdMeTech had considerable impact, as well they should have. Fay was one of the early pioneers of imaging as a key component in the battle against breast cancer. Many women can thank her for their improved quality of life. We are very fortunate that her AdMeTech Foundation has taken up the battle for better imaging on behalf of men.

    Dr. Richard Sorace of the Dattoli Cancer Center showed off the considerable abilities of their “Star Wars”-like IMRT targeting system. Richard made it very clear that patient results are highly dependent on accurate imaging, driving home the point that we desperately need an imaging agent that can pinpoint cancer at its earliest stages and we need it now.

    Us TOO International sent Dave Houchens to represent their group. Dave’s own experiences battling prostate cancer certainly added credence to his comments. It was a pleasure having a fellow cancer survivor with us.

    Orn Adalsteinsson’s work as the founder of ISCA , his background in biotech, and his PhD from MIT uniquely prepared him to work behind the scenes with AMAG. Having someone with Orn’s credentials speaking to AMAG on our behalf was certainly very helpful. This is a business and it’s a big business. Saving lives or not, AMAG needed to understand that we were there to get results. Orn helped drive that point home.

    Dr. Jelle Barentsz did an outstanding job of moderating his own presentation. I don’t think I’ve ever attended such a well received presentation. His ability to seamlessly incorporate the comments of so many of his colleagues created a presentation that seemed to include virtually everyone in the room. Jelle’s passion for the subject at hand was self evident. By far this was the single best presentation I’ve ever had the honor to be a part of.

    I think Jelle was able to accomplish the goal he must have set for himself before embarking on a journey that held many challenges, not the least of which was crisscrossing Europe and the Netherlands to avoid volcanic ash clouds that had grounded many flights. By the end of his presentation he was able to impart to the audience both the human, very desperate need for this technology and the science behind it all. More than anything else, our hosts could see that we were there to truly save lives and that they could play one of the most important parts of all.

    I would like to give a very special thank you to Stephen Strum. His can-do spirit and passion was embodied in all who worked to make this happen. While he couldn’t physically be with us, his spirit, passion and concern for humanity certainly filled the room. Thank you Stephen.

    From the perspective of a patient advocate, things could not have gone better. Now it’s time to get to work and produce results.

    Where are we now? by Jelle Barentsz:

    AMAG will provide Dr. Harisinghani and me with Feraheme. Dr. Harisinghani (MGH, Boston) will focus on pancreatic cancer. I will do a validation study for nodes in prostate and urinary bladder cancer. In this study, 40 patients will be enrolled with primary prostate or urinary bladder cancer. They will undergo a Feraheme MRI, and subsequently will have their nodes surgically removed. The results of Feraheme can be then compared directly with histological results. Additionally, I will give the contrast agent to 20 patients who in the past year have had Combidex and this will allow me to compare the effect of the agent. This particular study will take about 6 months.

    After successful completion of this “validation study,” other studies will be initiated by me and by AMAG Pharma, which will be focused on getting FDA approval for its use as a nodal diagnostic agent. These studies will include a US-European study with UCSF (Dr. Roach), MGH Boston, and Nijmegen on selective radiotherapy in patients with advanced prostate cancer, and a Dutch multicenter study in axillary nodes in breast cancer.

    Until there are favorable results of the validation study, use of nanoparticle MRI is not possible — not even in the Netherlands with me.

    The validation study is entirely funded by my department. AMAG Pharma only provides me with the contrast agent. If financial support is provided, however, I could speed up the work considerably; more funds would enable faster use of nanoparticle MRI for nodal imaging. Therefore, I would appreciate any donations. The support through the patient advocacy group is also needed and I would be grateful for it.

    Kind regards,

    Jelle Barentsz, Professor of Radiology
    Department of Radiology, Radboud University Nijmegen Medical Center
    Nijmegen, The Netherlands

  18. OK. This is all very well, but Feraheme (ferumoxytol injection) is not the same as ferumoxtran-10.

    Effectively, what this means is that Dr. Barentsz is starting all over again to see if Feraheme can be used in a manner similar to Combidex/Sinerem. I don’t even pretend to know whether that is actually feasible. What I do know is that it is likely to take several years to demonstrate whether this is actually possible, and if Feraheme is ever to be widely used clinically as an agent to help identify the presence of positive lymph nodes it will require randomized, Phase III clinical trials and data that is acceptable to the regulatory authorities in the USA and in Europe.

    Unless AMAG is interested in funding those Phase III clinical trials, the chances of widespread use of Feraheme as a diagnostic imaging agent is liable to be low — even if the clinical results of the trial Prof. Barentsz is proposing are striking.

  19. I have been on hormone therapy since 2005. It has caused me to become disabled. I have memory problems; I have a lot of joint pain; I have become weak; I have no energy; I get hot flashes; and I never feel good. Is there some way to stop this treatment and keep the cancer from growing? I have been told I have to stay on Trelstar or Lupron until it stops working … and then I have 22 months to die.

    Walter Wilder

  20. Dear Walter:

    I strongly suggest that you join our social network, where you will be able to communicate with other patients who may be able to offer you other suggestions, depending on additional information that we would also want to ask you (e.g., your age; any prior treatments; your current PSA level; and some other stuff).

  21. Can someone help me locate a physician that would radiate if an isolated lymph node were located on a feraheme study. My father, who is young, had a feraheme study after RP and pelvic radiotherapy and has a single lymph node above his radiation zone however finding a physician to radiate in the northeast has been difficult.

  22. Dear Ken:

    You might have better luck if you joined our social network and asked the question there. The exact position of the lymph node in question may be a big issue, however.

  23. I will join the network. the location of the node is by what i’ve been told not difficult to radiate (paraaortic node) but since it is not standard of care most would prefer not to radiate. Would love to find someone who has had it done and by whom…

  24. Make sure you put that info into the entry on the social network.

  25. Ken, I am in the same boat. I was with a leading physician today at Roswell Park Cancer Center in Buffalo, NY and I have two lymph nodes that were positive out of nine that were taken out during radical prostatectomy. I have asked several doctors about a test to determine what other lymph nodes have cancer so as to be able to either radiate them or take them out and they tell me we do not surgically remove them and they do not target them directly. I am a 48-year-old male, pT3a, Gleason 4 + 3 = 7, PSA 0.08 after surgery. I would like a vaccine that could kill off any lymph nodes that are positive, like you.

  26. I am considering a Feraheme injection and MRI. Have any of you had experience with this procedure?

    I am trying to get as much information as possible because I understand there is a big risk to the individual having this done.

    Thank you

    Charlie

  27. Charlie:

    I have not personally had this procedure, but you might want to carefully review the full prescribing information for Feraheme, specifically including the sections on “Warnings and Precautions” (see Section 5) and “Adverse Reactions” (see Section 6).

  28. Just yesterday, May 17th, I had a lengthy and detailed conversation with Dr. Solace of the Dattoli Cancer Center. I had contacted them about having a USPIO scan. After having had da Vinci surgery, SRT radiation therapy, and MET radiation therapy, my PSA still continues to rise.

    A recent discussion with other prostate cancer folks brought USPIO to my attention. I found information that this scan was being conducted by Sand Lake Imaging in Orlando, FL. When I contacted them I was told that while they perform the scan, they only do so on the referrals from two doctors. Dr. Strum and Dr. Dattoli. So I contacted the Dattoli center.

    I learned much from the conservation with Dr. Solace. It would seem that Feraheme has been approved for the treatment of iron deficiency anemia. It is therefore available to the public. If one were to have an MRI scan at the same time as having had a Feraheme injection the results of the scan would be enhanced in the same way as having had a Combidex scan.

    While the thought of being able to have this scan intrigues me, as I want to find out what is causing my PSA to continually rise, it seems to me that this is really skirting the FDA process. I would be necessary to pay for the Feraheme personally, while my insurance company would pay for a standard MRI procedure. While it’s benefit could be great, I am in fact paying for my own participation in what to me is a clinical trial.

    Further, my research in the last couple of days has found some real side effect issues with the use of Feraheme.

    I would appreciate your thoughts on this.

    Thank you

    Sonny

  29. Dear Sonny:

    I am not personally aware of any reliable data to suggest that the combination of Feraheme injection and an MRI can be used reliably to identify the presence of nodal prostate cancer metastases. The potential side effects of Feraheme, on the other hand, are well known. We don’t know the accuracy of this test in prostate cancer. We certainly don’t know the false positive or the false negative rates. And at the end of the day it is unlikely that the results of the test will make any difference to your therapy, because your next therapeutic option is almost certainly ito have to be hormonal therapy of some type if your PSA continues to rise.

  30. I read parts of the info on this site and have followed info from Snuffy Myers regarding the use of Feraheme to locate metastatic lymph nodes. I had a da Vinci RP in 9/09 where one lymph node in the iliac chain was positive. Since then, I have only used diet and exercise to limit increase in PSA, which has gone from 0.01 to 0.10 over a period of 24 months with the last two PSA test both being 0.10.

    I am interested in the possibility of needing follow-up radiation if the location of the prostate cacner can be determined. I am a physically active 67-year-old male in good physical condition with a positive outlook. So,

    (1) What are the side effects of Feraheme when only used for imaging?
    (2) Do we have enough study results to indicate that Feraheme helps locate metastatic lymph nodes?
    (3) What am I missing?

    Thanks, Ken

  31. Dear Ken:

    I am very biased. I like to see really clear data before I start suggesting to people that any new imaging test is really valuable. I haven’t seen such data in relation to Ferraheme being able to identify microscopic areas of metastatic disease with reliable accuracy. I have, however, heard what the cost is.

    I do not know what the risk for complications related to Ferraheme usage might be … but I don’t believe it is particularly risky. The problem from my point of view is that we are “missing” reliable, prospectively validated data that can tell us whether Ferraheme-based imaging is actually particularly accurate at identification of micrometastasis (to the lymph nodes or anywhere else).

    I would note that in your own case, if your PSA is now stable again at 0.1 ng/ml, then the chances are you shouldn’t be doing anything. It could remain stable at that level for years, and a formal PSA level recognized as implying biochemical recurrence is usually considered to be 0.2 ng/ml, not 0.1 ng/ml.

  32. Dear Ken,

    I would agree with the comments from Sitemaster. No imaging tests currently available can detect microscopic disease and with your PSA at 0.1 ng/ml; best to just keep monitoring your PSA.

    An ongoing, FDA-approved clinical trial using carbon-11 acetate PET/CT in Phoenix, Arizona, which I am involved with, is showing that we are able to detect recurrences (in the prostate bed, lymph nodes, other organs, and bone) fairly reliably when the PSA is above 2.0 ng/ml (> 90%). With lower PSAs in the 0.2 to 1.0 ng/ml range the ability of the test to detect disease falls off to about 50% to 60%. These are preliminary findings, and we will be evaluating this with several hundred patients over the next few years.

    Carbon-11 acetate images the tumor cells by looking at their lipid metabolism. And, with PET imaging, a large part of the body is imaged (from the neck through below the pelvis).

    With feraheme MRI, normal lymph nodes take up the feraheme, while abnormal ones don’t. It is not specific for cancer and the false positive rate will be high, as was shown to be the case with Combidex (24% false positive rate). It would be expected that feraheme would be no better. What this means is that with feraheme about one-fourth of the time it will be wrong, leading to possibly unhelpful additional surgery or radiation therapy.

    Also, MRI typically is only done of the pelvis and lower abdomen. We find that with carbon-11 acetate PET/CT we see early metastatic disease outside of the pelvis (with no disease in the pelvis) about 20% to 30% of the time; these are missed by MRI (with or without feraheme)

    Similar results have been seen with carbon-11 acetate at Kansas University (they are no longer doing it due to new FDA rules for making carbon-11 products but may restart later this year), with c arbon-11 choline by the Mayo Clinic in Rochester, and in most of the recent work done with these agents in Europe. More to come, as we continue with our clinical trial investigation. …

  33. Thanks for the additional input Dr. Almeida. Very helpful.

  34. Dear Sitemaster:

    Any update about feromoxtran-10? When are they going to reproduce it? Are there any other companies producing similar agents? Were there any major side effects that made FDA decide not to approve it?

    Thanks

  35. Dear Basha:

    The reason that Combidex never got approved in the USA was complicated and had more to do with what the company that made it wanted to get it approved for than with any side effects. The trials that were carried out did not justify the precise indication that the company was seeking.

    As far as I am aware, no one else is trying to get this product approved now. It is likely that the cost to get the product to market now would exceed any possible economic return on the investment.

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