The ULTRA (Ubenimex) Clinical Trial for lymphedema failed as expected – but there’s still hope

By: Ryan Davey, PhD
October 17, 2018
Editors: Ryan Davey, PhD and Lindsay Davey, MScPT, MSc, CDT

Eiger BioPharmaceuticals published a press release yesterday announcing that their ULTRA Phase 2 clinical trial investigating Ubenimex for lymphedema did not achieve their endpoints, and that they would not be pursuing additional clinical trials at this time.

The ULTRA trial was designed to evaluate the possibility that the drug known as Ubenimex (also called “bestatin”) could be useful for reducing the symptoms of primary and secondary leg lymphedema. Specifically, they were looking at changes in skin thickness and excess fluid volume in 46 lymphedema patients treated with either 150 mg of ubenimex three times a day for 24 weeks, or placebo pills.

Eiger Ubenimex Ultra Lymphedema Clinical Trial Results Press Release

Unfortunate, but not unexpected

The company concluded that their clinical trial:

“demonstrated no improvement of ubenimex over placebo in the primary endpoint of skin thickness and secondary endpoints of limb volume and bioimpedance”

It’s an unfortunate outcome. Ubenimex is a safe drug that has been approved and used in Japan as a chemotherapy adjuvant for over 35 years, and early mouse studies for lymphedema were certainly promising. But we’re not surprised by this result.

As we reported in-depth last year, the excitement surrounding Ubenimex was overblown in the first place. Published press releases and interviews at that time misrepresented the results of the primary animal study underlying the clinical trial, and in doing so set unrealistic expectations. Communicating research data in an exaggerated way to attract attention is understandable and perhaps even unavoidable. But designing a clinical trial with questionable connection to the underlying research is a little bit more baffling.

As we reported last year, the research underlying this clinical trial suggested that:

“Ubenimex (bestatin) may help NEW lymphatic injuries heal, but ONLY if natural healing is biologically possible, and ONLY if it is given at the right time and right dose. In contrast, the press release implicitly suggests that bestatin may reduce the symptoms of lymphedema regardless of the underlying plumbing problem and divorced from the normal healing process – which is not supported by the available data.”

Stated simply, available data tells us that we should only expect Ubenimex to have an effect if natural healing processes are active, and healing is possible.

Therefore, Ubenimex MIGHT be expected to:

  1. Help prevent the onset of secondary lymphedema by encouraging the natural healing process.
  2. Help prevent lymphedema progression in primary and secondary lymphedema by helping natural healing processes deal with ongoing inflammation and injury arising from unmanaged fluid accumulation.

But this is not what the clinical trial investigated.

I get it, establishing a role for Ubenimex in lymphedema prevention is MUCH more difficult (and therefore expensive) to investigate in a clinical trial. But the available data does not support the hypothesis that they decided to evaluate in their clinical trial, namely that Ubenimex could reverse symptoms in established (and presumably well-managed) cases of lymphedema.

No doubt Eiger BioPharmaceuticals had a rational business case for running the trial, and perhaps it was inexpensive enough to warrant a Hail Mary attempt, but they shouldn’t be surprised by the outcome.

There may still be something exciting here

I was thrilled that a pharmaceutical company decided to fund a clinical trial for lymphedema, and hopefully this will spur others to consider this untapped market. Kudos to Eiger BioPharmaceuticals. More importantly, the underlying animal research behind this trial is very well thought-out and exciting, and I’m certain the authors will continue down this road. The research is particularly exciting with respect to preventing symptom onset and/or progression.

Eiger BioPharmaceuticals also reported that their results might suggest that some individual patient responses could be interesting enough to warrant further exploration (but not by them), and that they would be open to further clinical trials if someone else came to the table to help support them. This may simply be the company trying to save face, but it wouldn’t surprise me if there were truth to these statements.


  1. Canada MALE (Male Advocate for LymphEdema) aka Steve Kelland...LE&RN: Canada Chapter, Chair Canada MALE (Male Advocate for LymphEdema) aka Steve Kelland...LE&RN: Canada Chapter, Chair says:

    Great piece – this ‘contextual’ presentation is helpful for realistic optimism going forward. The #LE (Lymphedema) Community does not need processes where there is what the military often refer to as ‘situating the estimate’. We need realistic prospects of help, with every potential of hope!
    Thank you, Toronto Physiotherapy, for the ongoing efforts for THE Community, which (since establishment of “World Lymphedema Day – 6 March 2016) no longer recognizes national boundaries in its fights vs this progressive, chronic, oft-debilitating & socially stigmatizing “scourge” for which there is (yet!) no cure. ✌️
    Good health – Canada MALE (Male Advocate for LymphEdema) | FB: Lymphedema – LE Nexus Canada ✌️

  2. Deb Deb says:

    Thanks for being so quick to get a piece out that aids our understanding of what happened here, Ryan. Your synopsis is right on. I believe there is definite reason to remain hopeful, but we must remember more research time is still needed to improve the basic understanding of the lymphatic system in health and disease compared to what is understood in other body systems/diseases that have many medical treatment options available. But these research endeavours are not wasted! They are contributing to the basic lymphatic system understanding, as well as knowledge of treatment paths to refine! It is important for us all to remember: 1) Not to lose hope; 2) That the world is currently “catching up” on basic lymphatic system research; 3)That some of the world’s most important research discoveries have been revealed in the most serendipitous and unexpected ways. Thank you for your continued support of the lymphedema community Ryan!

  3. Robert Jensen Robert Jensen says:

    Over a year ago, hence my vague recall of the details, I read where there is another drug being investigated by a doctor in France or Belgium that shows promise. This supposedly is not some type of NSAID like Ketoprofen.

    Have you read anything about this and what it might mean for us suffers?

    • Hi Robert,

      Sorry I’m not sure which drug you might be referring to, perhaps it could have been in an animal model. There are a lot of drug ‘candidates’ investigated in very preliminary studies, but few make it to human trials. If something comes up that looks interesting I’ll be sure to review the data here!

  4. Tony Chianese Tony Chianese says:

    It seems odd that a PHD would be negatively analyzing the work being done by a serious group of dedicated doctors, seeking answers that you state as ” ULTRA (Ubenimex) Clinical Trial for lymphedema failed as expected”.

    • Thanks for your comment Tony, you bring up an interesting topic. When it comes to scientific research, peer review is a necessary and vital component of the scientific process. A lot of very serious and dedicated doctors and scientists publish failed studies, soon to be disproved hypotheses, and contentious data each year. It is up to the scientific community to wade through it and to be critical of it – it is part of the self-correcting process of science. In my opinion this trial was bound to fail from the start, and I’m sure I was not alone in expecting this. But that doesn’t mean that it wasn’t worth trying! Scientists are wrong all the time! But don’t worry though, these researchers will not feel personally attacked by my comments. As I learned when I was publishing my own primary research, you develop a pretty thick skin!

  5. Karen Karen says:

    Thank you for your very clear evaluation of the reasons why the clinical trail failed, thereby dashing hopes for many with a more advanced stage of lymphedema. What is difficult for me as a cancer exercise specialist is to see doctors pin all the hope on drugs rather than prevention and there is a great deal that can be done to prevent secondary lymphedema. So, I also agree with you that if the drug can help prevent the disease that in itself would be a huge success, since we know that many people who go through certain cancer treatments are at a high risk for developing lymphedema. 

  6. Joy Joy says:

    If Bestatin has been used safely in Japan for over 35 years, it should be available for use in the USA and Canada. It should be a choice between doctor and patient.
    There must not be any money to be made with Bestatin by Big Pharma, just like there’s no money to be made w hydroxychloroquine. Hydroxychloroquine is generic. The patent has run out. It’s a cheap treatment. Big pharma doesn’t want that! 

  7. As this article was published in 2018 has there been any further advancement on Ubenimex (Bestatin) for Lymphedema please. I had endometrial Cancer Stage 1 and had a robotic Hysterectomy and Salpingoophrectomy in October 19. they removed all my pelvic lymph nodes as they were all enlarged only to find out later I had a rare condition Rosai Dorfman Disease (Sinus Histiocytosis) that is benign. My problem is lymphedema particularly in my left leg which causes severe pain in my upper left thigh and my buttocks. I have back ache where I don’t walk properly, wear compression leggings which are extremely hard to get into as I have had Rheumatoid Arthritis for almost 50 years and would like to have info on this drug. living in Britain it is extremely hard to get info. I would be extremely grateful for any info.
    Kindest Regards Cheryl

    • Hi Cheryl,
      Unfortunately, there have been no further results published, good or bad. Conventional lymphedema management practices are still your best option.
      Best of luck with everything Cheryl!

  8. Joy Joy says:

    Have there been any positive studies on treating lymphedema with horse chestnut?

    • Hello Joy,
      To date we have not seen any peer-reviewed literature on the treatment of lymphedema with horse chestnut, no. I hope that further continued exploration and investigations will someday produce evidence that supports alternative approaches to the treatment of this condition. Thank you for your comment! Lindsay Davey

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