Daiichi Sankyo’s big, big bet on fibromyalgia failed.
It must have seemed like a done deal. Daiichi Sankyo was so confident that its safer, more effective version of Lyrica (pregabalin) called Mirogabalin was going to beat the pants off the best-selling drug for FM. How confident were they?
- They funded easily the largest FM trial ever – 3,600 patients in 300 centers throughout North America, South America, Eastern Europe, Western Europe and the Asia Pacific region.
- To make it completely clear how much better their drug was than Lyrica, they even included a Lyrica arm in the trial.
- They jumped straight into their huge phase III trial without doing a phase II safety and efficacy trial first.
They were going to spank Lyrica in the U.S. and – in places where neither Lyrica nor any other drugs have been approved for fibromyalgia – they were going to get that coveted first drug approval slot.
Of course they had reason to be confident. Lyrica, Mirogabalin’s predecessor, binds to a calcium channel subunit that does reduce pain levels but has also been implicated in producing the many side-effects Lyrica is notorious for. Many people quit Lyrica not because of it not working but because it produces too many side-effects. Mirogabalin, on the other hand, binds to a different, putatively safer calcium channel subunit that was believed to only reduce pain levels.
They’d painstakingly targeted a part of the central nervous system that was clearly involved in pain production. The drug had aced its animal trials – including an FM animal trial. Their Phase II peripheral neuropathy diabetes results were promising. Plus, mirogabalin was an upgraded version of Lyrica, which, in turn, was an upgraded version of Gabapentin, and Lyrica had been a roaring success… How could they go wrong?
Daiichi must have felt they were about to run an inside straight: they had what they believed was a more effective, safer drug that lasted longer than its main competitor as well. Plus, they’re were going to be first in major markets which had no approved drugs for FM. They could probably see the money rolling in.
Devastating Results
They results were devastating, however… Not only did mirogabalin fail to beat the placebo in any of the three large trials Daiichii ran, it failed to beat Lyrica as well. While some of the secondary endpoints were successful, others weren’t. Plus, to add insult to misery, Lyrica beat the placebo in two of the three major trials Daiichii funded.
Don’t feel too bad for Daiichi, though. Yes, they wasted a ton of money, but after abandoning FM, Daiichii Sankyo went on to fund successful phase III trials in peripheral neuropathy in diabetes and post-herpetic neuralgia. The drug did work – just not in FM.
Postmortem Report
Recently, a rare postmortem report, “The mirogabalin ALDAY phase 3 program in pain associated with fibromyalgia: the lessons learned“, was published by the senior author, Domenico Merante, of the big FM trial. That report followed a 2019 paper, “Fibromyalgia: An Urgent Need for Harmonized, Global, and Patient-Centric Regulatory Guidance for Developing Medications for the Treatment of Pain and Associated Symptoms“, which took the FDA to task for employing what Merante and Patel believed were the wrong outcome measures for fibromyalgia.
Note the word “urgent” in the title. Only three drugs are approved for FM in the U.S. – all of which have significant shortcomings. Two drugs are approved in Canada and none in Europe for FM. This is a disease that urgently needs better drugs.
The papers gave us a peek inside some of the pitfalls that await drug trials for FM and other pain conditions. The authors recognized that overconfidence played a role – a major role – in their defeat – but that was not why they wrote this paper. They wrote it to put the FDA on the spot.
Overconfidence
- The fact three big trials Daiichi funded for FM proceeded simultaneously was a big mistake. That left the drug company no room for any adjustments if one trial went bad.
- Daiichi never did a phase II safety and efficacy trial in FM, but instead expected results from a diabetes peripheral neuropathy (DPN) trial to hold. That was a problematic decision as FM is much more complex than diabetic peripheral neuropathy. DPN is caused by damage to the peripheral nerves. While small fiber damage does occur in FM, recent studies suggest it is of a different type, than in diabetes. Plus FM, with its central nervous system pain amplification problems, and the large number of other symptoms associated with it (sleep, cognitive issues, fatigue) is a far more complex disease.
High Placebo Response
Plus, the high placebo response seen made getting a positive result more difficult. Daiichi was prepared for a high placebo response – high placebo responses are common in pain drug trials – but the placebo response in this trial exceeded their expectations.
FDA Changes
Then came the biggie – understated in true scientific fashion.
“It remains unclear whether ADPS and W-ADPS correlate in fibromyalgia clinical setting. So far, the two pain scoring assessments have not been compared in an adequately powered study design in people with fibromyalgia.”
Prior to 2014, the FDA accepted a variety of endpoints (average daily pain score [ADPS], Patient Global Impression of Change, Brief Pain Inventory) to assess drug effectiveness in FM. In 2014, however, the FDA recommended that a new pain measure called the “weekly average worst daily pain score” (W-ADPS) be used. W-ADPS takes an average of the worst daily pain scores over a week. In other words, the patients assess their worst pain daily which the researchers compile into weekly averages.
The Daichii Sankyo trial was truly and epic failure. Did something the FDA did inadvertently contribute to that?
The authors argued the FDA made a fundamental error by insisting on this new measure. They asserted that assessing one’s highest pain score is not easy task and suggested that some people prone to catastrophizing would overestimate how much pain they were in – and possibly tank the study.
After assessing the past studies, the researchers were unable to find any correlation between the average highest daily pain score and the patients “average daily pain score”. Twice before – in a conference presentation and a paper – they speculated that using W-ADPS as the sole primary endpoint could result in effective drugs not being approved for FM. The FDA, they asserted, introduced a critical endpoint – upon which the fate of the trial rested – without any confirmatory data that the endpoint was effective in FM.
They concluded that the W-ADPS could be used but not as the primary endpoint, and suggested that past pain assessments such as the Brief Pain Inventory or the Fibromyalgia Impact Questionnaire were probably more effective measurements.
Different Measures: Different Results?
The authors acknowledged Daiichi had blown it by not exploring mirogabalin’s effectiveness in a smaller phase II trial, by not staggering the three mirogabalin FM trials, and by assuming that what worked in diabetic peripheral neuropathy would work as well in FM.
The Gist
- Daiichi Sankyo, a Japanese drug company, produced the largest ever fibromyalgia drug trial a couple of years ago.
- The monster effort included three separate clinical trials spread over three continents containing over 3,600 patients.
- Daiichi was seeking to displace Lyrica in the U.S. and Canada and provide the first FDA approved drug for fibromyalgia in Europe – and get approval for the drug in Asia. Daiichi even included a Lyrica arm in the trial in order to demonstrate the superiority of its product.
- The drug – mirogabalin – was an upgraded version of Lyrica – the best selling FM drug in the U.S. Daiichi believed its new formulation would provide better pain killing with less side effects.
- The trial was a bust. Not only did mirogabalin fail to provide more benefits than placebo, Lyrica, it’s arch competitor, provided significantly more benefits than placebo; i.e. Daiichi actually proved that Lyrica was better than their drug.
- A paper explored the reasons for the drug’s costly failure.
- Presuming that the results from another pain trial would show up in FM as well, the company failed to do a smaller phase II trial to assess safety and efficacy.
- By running three large trials at once, the company didn’t provide itself the ability to alter the trial if something went wrong.
- A higher than expected placebo response also impacted the results
- The authors, however, pointed to a decision by the FDA to change the primary end point it recommended for FM clinical trials. The primary end point is the one measure that a drug has to achieve.
- In 2014 the FDA recommended that trials not use the “average daily pain score” measure and instead use the “worst daily average pain score” for their primary endpoint.
- The authors warned that this seemingly small change may prevent effective drugs from reaching FM patients.
- They asserted that not only is it more difficult to assess one’s worst daily pain score but that people prone to catastrophizing are more likely to report higher pain scores than they would with the average daily pain reports.
- The authors also found no correlation between the average daily pain scores and the worst daily pain scores.
- Using the average daily pain score they found that patients taking the highest dose of mirogabalin were significantly more likely to achieve a 50% reduction in pain and an improvement in sleep than the placebo group
- While it’s not clear that mirogabalin would have been improved if the average daily pain score had been used, the authors clearly believed it might have.
- Noting that the U.S. has three FDA approved drugs, Canada has two and Europe none the authors called for a global regulatory system to assess drug effectiveness in FM.
They did suggest that the results might have been different, though, if the trial’s success had been measured by the average daily pain score instead of the average daily worst pain score. FM patients taking the highest dose of mirogabalin (30 mg/day) in their trials were very significantly (p = 0.0048) more likely to have experienced a 50% drop in pain than the placebo group. Plus, that group also had reported significant (p = 0.0001) improvements in sleep interference, and a significantly (p < 0.02) greater percent of patients reported that their overall health status was ‘much improved or better’ or ‘minimally improved or better’ (on the Patient Global Impression of Change [PGIC] scale).
Whether or not that would have been enough for drug approval was unclear, and it should be noted that even though mirogabalin was touted as a safer, more effective form of Lyrica, withdrawal rates of about 25% – mostly because of the side effects experienced – indicated that the drug was hardly without-side effects. Even under the different testing regimen patients receiving a smaller benefit (30% drop in pain) did not beat the placebo.
Still, one set of patients did very significantly benefit. It’s sobering to think that a potentially helpful drug for FM is now off the market for good because of a regulatory change.
The authors pointed out that the differing regulatory regimens across countries have resulted in different FM drugs being approved in different countries – and called for a “global harmonized approach” that recognizes industry, research, and patient needs.
Video Blog
Some people thought that video blogs might make the blogs easier – so here is the first one – a 15 minute or so video explaining the blog. Please note that these are entirely unrehearsed and unscripted. They’re basically one-shot takes with all that implies – lots of uhs, pauses, etc.
This is also the first one. The learning curve was steep – it took two days just to begin to learn how to do this – and the audio doesn’t quite match the video – a problem that probably occurred during the compression phase. (The video has to be compressed to reduce data usage before uploading.)
The video took, by the way, 15 minutes to make, 2 hours to compress and an hour and a half to upload to Youtube! That’s kind of untenable. Suggestions on how to reduce that are welcome!
Conclusion
The mirogabalin saga is a cautionary tale of the twists and turns a drug can meet during the approval process – something we’ve seen in abundance lately.
Lacking the money to do animal and other testing, Pridgen had to reduce the dose in his phase II antiviral combination FM trial to get FDA approval to move forward. Tonix turned its back on the TNX-102 drug until it worked in a higher dose for another condition – at which point Tonix reassessed and decided to move forward with a big FM trial. The Synergy ME/CFS trial failed, in part, because of the very strong placebo effects found. (A subsequent open-label trial in Gulf War Illness was successful. ) Some researchers believe the Rituximab ME/CFS trial failed it had too low of a maintenance dose.
Mirogabalin is not going to be approved for fibromyalgia and it has not been approved for any diseases in the U.S. It was, however, approved for neuropathic pain and postherpetic neuralgia in Japan in January 2019, and if it gets approved for either condition in the U.S. or elsewhere FM patients may get access to it that way. A savvy ME/CFS/FM doctor will know to look behind the numbers and determine for themselves what might work.
Omg, I loved this video blog, and it’s great to see your face!
Thanks…I don’t know what to think actually but thought I would give it a go.
Good first try on the blog! I don’t think I could even get something like that downloaded!
However, I am smiling to myself as I think you sound much like me trying to explain things. For some odd reason, I come across much more organized when I write. Please don’t that that as a criticism, just an observation.
It was nice to see who is behind HealthRising, and very nice to get that wonderful view of nature and River!
Interesting about people who have strong placebo effects. I wonder if they are the type to also better respond to hypnosis? I could imagine some sort of pre-clinical trial sorting of participants into those who are ‘more suggestible’ and those who are ‘less suggestible.’
Drug trials are so difficult. Beware the statistics! Then there are always those whose genetic make-up etc. may determine how successful or not any particular drug may be. I’m sure there are sub-sets of fibromyalgia as well. It still doesn’t bode well that there was that 25% of people who didn’t tolerate it, and it likely that many with fibromyalgia are drug sensitive anyway…
So, don’t let my comments dissuade you with the blogs! Decent first go!
So much easier to be organized on paper. I’m afraid organization will suffer. It was nice to get River in there!
I agree. I hope this prompts drug companies to stop mining the gabapentin-Lyrica-Mirogabalin pathway and turn to something better. Of course, like sequels in movies, it’s a lot easier to tweak something than create something newly.
Taking a different angle, I see two major problems in the Daichi approach and the FDA regs:
1. The effort was a new twist on the old pharma stunt of tweaking a molecule to capture a market, rather than involving serious science on disease cause and possible new curative mechanisms.
2. FDA and indeed all medical science needs to be focusing on replacing self-report data in clinical trial evaluations with approaches that minimize subjectivity. This might involve some sort of nano-pin pricks to test pain suppression, for example. It must involve activity measurement meters for all issues surrounding recovery from ME and CFS. And so on. To paraphrase Gilbert and Sullivan, “Our endpoints all sublime, we shall achieve in time; to make the measurements tell no lie, the measurement tell no lie.”
Agree on both points. Mirogabalin was probably going to go only so far anyway – particularly with FM. I imagine everyone in the drug industry yearns for objective measures. Here’s to Dr. Bateman’s “feet on the floor” measure to win out in ME/CFS. It’s not a blood test but also not a subjective assessment.
Yes, Dr. Bateman’s “HUA” (hours of upright activity) is described here at minute 2:50
https://m.youtube.com/watch?feature=youtu.be&v=oTfOie4rVvw
Any lawsuits on Tramadol? It gave me megacolon, which still causes me problems although I stopped taking it in 2014.
Thanks, this is a good summary of Clinical Trials in general, and what can go wrong.
I agree with comments that it would be better to reduce subjectivity in measuring pain outcomes in clinical trials. But, in fact, the FDA has recently placed more emphasis on using patient-reported outcomes, especially for pain conditions, when considered drug data for approval. This is because the efficacy of a drug goes beyond its ability to decrease pain, and this has been clearly demonstrated in conditions like rheumatoid arthritis, which affect quality of life beyond just pain. Unfortunately, while this mindset is great, it doesn’t help for FM if we can’t even get to the point of having a meaningful, validated pain scoring scale. There are tons of pain scales employed for autoimmune/rheumatological conditions (mainly RA) that work super well. Not sure if they have been tested/explored in FM but I don’t know why no one has looked at that. I find it stupid of the FDA to insist on using W-ADPS as a primary endpoint if it isn’t validated or even shown to correlate with ADPS. If you can’t demonstrate the sensitivity of an endpoint to detect meaningful change with an intervention/treatment, then it makes no sense to use it.
Also, I don’t know why Daichii didn’t think about that when designing the trial protocol, and instead include other co-primary endpoints. As Cort explains, if another one had panned out at least it would show something useful. The PGIC, FIQ, EQ-5D, and SF-36 outcomes work successfully for many other pain conditions, so that could also be why some of them showed success as secondary endpoints here (maybe they are better instruments to measure change!)
I also still think all FM trials are pretty doomed to fail because we still aren’t diagnosing people properly and people falling within the umbrella term of FM likely have different conditions or different subsets of one overall cluster of syndromes. By trying to accrue so many patients as was done in this trial, I guarantee there were more people included who may be misdiagnosed and not even have FM at all.
By doing this, it dilutes the sample and makes it impossible to get much statistical significance, and that will always then minimize the benefit:risk ratio you can get with drugs that are bound to have side effects. If we could get better diagnostics or more stringent eligibility criteria for these trials, maybe that would help.
I also agree that this doesn’t target or address any of the underlying causes of FM. However, it is unlikely that pharma companies will want to sink money into something so complex. I, for one, would be happy to have a better drug to at least make symptoms somewhat more manageable. I think Mirogabalin still holds promise but probably not for US patients at this point, maybe in other countries with different regulatory guidance on what is meaningful. I wish Daichii had done a Phase II and been able to then adapt trial conditions before going into Phase III 🙁
Loved the video format, Cort!! Hope you’ll keep doing them. And thanks for sharing some footage of New River and your dog. I love that area, and I’m considering relocating there in the next year or so (Carefree/Scottsdale) — would love to be in a drier climate. Thanks and keep up the great work, Cort.
This didn’t sound very exciting anyway. I’m tired of drugs that are just remade to be a more expensive version of a generic that is already available. And Gabapentin and Lyrica aren’t really wonder drugs for fibromyalgia. I’m waiting for the drug breakthrough that is going to actually help me get well. To not just ease pain but cure my fatigue and flu like symptoms. Currently Kratom works wonders for my pain and doesn’t have the side effects of most of the many other drugs I’ve been given. I’m still hoping for a cure, not just a new and improved version of a drug I don’t tolerate anyway.
If high resolution isn’t a priority, the simplest way to make a video is to record it on your phone (best done somewhere quiet or inside), then upload it to YouTube. I do this for poetry to upload to Instagram.
The format isn’t widescreen and you can’t edit the video much, except choosing where to begin and end, but it’s a quick and easy way to get started as you don’t need any expensive equipment or editing programs.
I like the idea of the video blog and it was nice to see your face (and very cute dog), and beautiful countryside.
I couldn’t get any sound, though. I kept tinkering with my computer and with the controls on the video, and could hear some very faint sound in the background but not enough to tell if it was even a human voice, although I could see your lips moving.
Did anyone else have this problem? Any suggestions?
Thanks.
Boy. We had this problem earlier but thought we got it fixed – but not apparently for everyone. This is a learning process, for sure.
Please don’t stop doing the writing too! I can’t hold on to info from a video or audio, so I count on the written word. But I know many others are the opposite. It adds work for you to do both–but oh how I wish those 5 min. messages from OMF, BHC, SMCI, etc. would have a transcript as well.
Thanks for all you do, Cort.
Interestingly I looked at the FDA guidance website today and that guidance they issued back in 2014 for development of pain drugs, which is what influenced Daichii’s decision to use the W-ADPS endpoint in this trial, has since been withdrawn!!
I’m not sure who it was thinking video blogs will make it ‘easier’-
Harder to think when upright, on the spot, aerobic exertion from speaking, no time to piece together thoughts- harder for you
Video blogs take more work editing and uploading than anyone realises too
And then lots of people can’t watch cos of sound and light issues, plus it takes longer to watch videos cos you can’t scroll through
It’s nice to see your face but honestly I’m not sure it’s worth the extra effort for you!
When I first read that you were doing a blog I thought immediately how much better it would be for many of us. Reading is so difficult for so many. Great idea!
hello Cort and every body,
I hope you continue to write because I don’t understand English. I am french, and fortunaly Google chrome done automatically the traduction, but not for videos.
In France, there is no magic solution EM/SFC.
What helps me when I am in crisis, it’s a lot of rest and acupuncture. The acupuncture lot of help.
Daily, I do a little gardening or little electric assistance bike, I don’t eat too much sugar or gluten or dairy. So, I can work part time ( sometime is difficult).
I do not support drugs or food supplements.
A big thank you for your work Cort, it’s masterful.
Simply fascinating. Thanks so much for sharing this and for all you do to support those of us facing this illness!
I’m waiting for a nerve pain drug that doesn’t have diarrhea as a side effect. So far, there’s only morphine.
I LOVE The Work YOU Are Doing! Thank You so much for Your Dedication and Commitment To Shedding Light on the subjects Necessary To Give Informed Decisions! Bless You Cort! I have no data to see the Video stuff so can not comment on it. Please let Us know about the Serious and Valid Studies, which I am a part of with Bodystream. A Medical Marijuana Facility which houses Knowledgeable Staff and REAL Dr.’s…The Ones Who Are Helping Humans Naturally Manage LIFE! IT Is MY Path.
Thank You! Keep Up The Great Work, Stay Alive and Well While Fighting for the Benefit Of Others.
Peacefully Living In Ontario, Canada
Namaste, Amen
I’m currently taking Tarlige 10mg (Mirogabalin) for neck and lower back pain. I currently live in Japan. I had a discectomy on my lower back between L4 and L5, there was nothing that could be done for S1 other than a steroidal shot. I was on Lyrica and Tramadol for approximately a year and a half. The combination started to have ill effects on my mental health and I needed more and more of each to combat the pain from 2013-2015. I stopped taking both and crashed. Luckily my wife helped me through the emotional roller-coaster. I have been dealing with lower back and neck pain for quite a long time. I believe that I have AS (ankylosing spondylitis) but none of the doctors here will confirm. So I try to deal with the pain using the Wim Hof method of cold showers and breathing. It does help, but every now and again I need something to get through the pain. I currently work from home so sitting and looking at a computer screen all day is not exactly helping my situation. I recently went to my local doctor and he suggested Tarlige 10mg. I don’t think that it is helping much. A side effect is drowsiness. So it does help with sleep. I came across this website trying to find info on Tarlige (Mirogabalin).
Hi Don, since I see you were taking Lyrica for a time and it likely helped, but the combination with Tramadol is what seemed to produce the side- effect, I hoped to just let you know Lyrica is not only a “patent” drug – it is now also available as a generic brand. So you can get just Gabapentin and not “Lyrica” (even though they are chemically the same thing) so it is now a lot less expensive (My insurance paid $770 a month for Lyrica, now I pay $35 (+/-) per month). So that is in case you would like to try taking it by itself, but was previously too costly. Hope everything goes well for you.
After seeing a world renowned FM/CFS (and AIDS) Doctor in Houston – Dr. Salvado, she checked my antibody levels for Epstein-Barr virus and they were very high. So I learned that this virus is exactly why I do have FM (and that about 90% of FM sufferers have it because of this virus hiding in the cheeks). She prescribed a recently developed antiviral med but I couldn’t tolerate it. So my regular Dr (at the time) let me try an older version of the same antiviral med (starts with a “V” but forgot the name). After I took a full dose my energy bounced back a huge amount (so I knew the doctor was right!). After the first several doses I felt almost as well as before I was previously tackled by it (all within a few days with unbearable fatigue – and unable to stand more than 10 seconds). I was ecstatic and couldn’t believe nobody else knew this!! But sadly the next month the fatigue began returning. It was only half as affective as at first. The next month was the same thing, and again less affective the next month – I was heartbroken. I also read of another gentleman who had the same thing happen to him. So I began reducing the antiviral a bit at a time and as I did so the fatigue, of coarse, was even more horrible. It was a very hard thing to keep reducing the medicine since the fatigue even affected my mind’s ability to think. I wished I had never taken it. I might have done so for a week or so in order to go on a family vacation or something but would not recommend anyone else try this specific route. The main point of this is to say, big Pharma knows exactly what and why and they very likely know the best kinds of drugs to research to actually stop the illness. But developing a drug to suppress only the symptoms is the motive behind I’d say 99% of the drugs they’ve ever researched and marketed. Yeah, we need them but they also need us – to stay sick, and that’s pretty sickening too.