Potential Fibromyalgia Treatment is Put on Hold

Potential Fibromyalgia Treatment is Put on Hold

By Donna Gregory Burch

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Donna Gregory Burch

The fibromyalgia community received some bad news earlier this week when Tonix Pharmaceuticals Holding Corp. announced TNX-102 SL (trade name: Tonmya), a low-dose, sublingual form of cyclobenzaprine (Flexeril), did not achieve the primary goal of pain relief in its latest clinical trial. The company will no longer seek approval from the U.S. Food and Drug Administration for TNX-102 SL, one of three new pharmaceutical treatments in the pipeline for fibromyalgia.

Lack of restorative sleep is one of the primary symptoms of fibromyalgia, and TNX-102 SL showed great promise for improving the slumber of fibro patients. Its developers theorized that if fibromyalgia patients could get better sleep, then it may lead to pain relief.

However, in the latest trial, TNX-102 SL failed to meet the threshold for pain relief. A high rate of patient dropouts not due to the use of TNX-102 SL contributed to the trial failure.

Below is a short Q & A with Tonix’s CEO Dr. Seth Lederman about what went wrong with the recent fibromyalgia trial and the future of TNX-102 SL.

Can you give me an update on the TNX-102 SL trial for fibromyalgia? I read that it did not achieve the pain relief goal.

The preliminary results from our Phase 3 clinical study, AFFIRM, designed to evaluate the safety and efficacy of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in patients with fibromyalgia, showed that the drug did not meet the main goal of reducing pain in fibromyalgia patients by 30 percent or more over a 12-week period. However, TNX-102 SL did show statistically significant effects on pain when analyzed by other standard statistical approaches.

TNX-102 SL activity in fibromyalgia was cross-validated by two additional endpoints, Patient Global Impression of Change (PGIC) and Fibromyalgia Impact Questionnaire-Revised (FIQ-R). These endpoints assess global improvement and a range of fibromyalgia symptoms and function.

TNX-102 SL showed strong effects on improving sleep quality by the daily diary and the PROMIS sleep disturbance scale. The internal consistency of these results provides clear evidence of beneficial effect of TNX-102 SL for the treatment of fibromyalgia.

What’s next for TNX-102 SL?

Despite achieving clinically meaningful results from AFFIRM, we have greater clarity on the regulatory path forward in our PTSD [post-traumatic stress disorder] program. We will therefore discontinue the fibromyalgia program in order to fully focus Tonix’s resources on advancing our potential breakthrough PTSD program to Phase 3.

I’m assuming this is a big disappointment for the company. Your thoughts?

Our decision to focus on PTSD was ultimately a decision between two appealing Phase 3 programs. We don’t have the resources to take both the fibromyalgia and PTSD programs forward, and since each program will likely require two Phase 3 studies for FDA approval, PTSD seems like the better option.

In our Phase 2 AtEase study, TNX-102 SL 5.6 mg showed significant improvement in PTSD measured by the Clinician Administered PTSD Scale (CAPS). PTSD is considered a serious mental illness, which is one of the criteria for breakthrough designation. We believe TNX-102 SL has the potential to be granted breakthrough designation since military-related PTSD does not appear responsive to currently approved medicines.

This is also a big disappointment for the fibromyalgia community since there’s such a lack of effective pharmaceutical treatments. Any thoughts?

While the study did not achieve statistical significance on the pre-specified primary analysis – where all patients who discontinued for any reason were treated as non-responders – there is clear evidence of efficacy in AFFIRM. We are gratified to see, in AFFIRM, strong positive effects on sleep quality and other clinical outcomes that are important to this patient population, as highlighted in the FDA-sponsored Patient-Focused Drug Development meeting conducted in March 2014.

These findings validate our approach to developing a differentiated drug that targets sleep quality and acts beyond analgesia to improve multiple symptom domains of a complex and inadequately treated condition. When we started our program, sleep quality was not regarded as a potential target of therapy in fibromyalgia. By establishing and validating sleep quality as a potential target of drug therapy in fibromyalgia, we believe we’ve shown the way for us and other drug developers to a new class of medicines that target this mechanism.

Can you please elaborate on the impact of the people who dropped out of the trial had on the data? 

There was an unusual disparity between the treatment and control arms in patient discontinuations unrelated to efficacy or tolerability–for example, a patient was moving to a different state so needed to discontinue the trial. There were 15 patients who dropped out in the treatment arm compared to three in the placebo group. This affected the responder rate, as drop-outs (like those moving out of town) were categorized as non-responders. In a responder analysis, you are penalized when people do not complete the trial. This directly led to the result we obtained, which was a near miss. If a couple of those patients had stayed in the trial, the results could have been different.

Is it possible that Tonix may re-pursue Tonmya for fibromyalgia at some point?

It is not possible in the foreseeable future as Tonix is now dedicated to moving forward with our Post-Traumatic Stress Disorder (PTSD) study, for which we hope to start enrolling patients in the first quarter of 2017.

There was an unusual disparity between the treatment and control arms in patient discontinuations unrelated to efficacy or tolerability. For example, a patient was moving to a different state so needed to discontinue the trial. There were 15 patients who dropped out in the treatment arm compared to three in the placebo group. This affected the responder rate, as drop-outs (like those moving out of town) were categorized as non-responders.

In a responder analysis, you are penalized when people do not complete the trial. This directly led to the result we obtained, which was a near miss. If a couple of those patients had stayed in the trial, the results could have been different.

Now it’s your turn? Are you disappointed that TNX-102 SL won’t be available as a treatment for fibromyalgia? Share in the comments!

Donna Gregory Burch was diagnosed with fibromyalgia in 2014 after several years of unexplained pain, fatigue and other symptoms. She covers news, treatments, research and practical tips for living better with fibromyalgia on her blog, FedUpwithFatigue.com. Donna is an award-winning journalist whose work has appeared online and in newspapers and magazines throughout Virginia, Delaware and Pennsylvania. She lives in Delaware with her husband and their many fur babies.

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Authored by: Donna Gregory Burch

There are 10 comments for this article
  1. Anne Fuqua at 5:43 pm

    The good news is that cyclobenzaprne IS already on the market and even available as a generic. If a lower dose option (that works have been greatly over-priced and again as a brand name – at least for the lower dose Tonix was developing. If you believe a lower dose would benefit you, there are a couple of options:

    1. Ask your doctor to write a script and get their recommendations as far as a lower dose goes. For strengths that only involve halving a pill, do this.
    2. If the dose is small enough that you would have difficulty getting an accurate dosage from splitting a pill, again talk with your doctor. If in agreement, ask for a script written for “compounded cyclobenzaprne xmg” and instructions for how many times per day to take it. Bring this to a pharmacy that compounds. They will use your physician’s instructions from the script to make the medication in the correct strength for you. So the other pills are not wasted many compounding pharmacies will not charge you for the actual drug, just the time and supplies needed to make the existing pills in the correct dose for you since you are just seeing if it helps you and you already have the cyclobenzaprne pills you can give them to compound.

  2. Steve at 8:32 am

    Interesting comments, though I kind of hate to be a frequent flyer and post again. When I declined the study, I tried cutting the cycobenzaprine into 2 mg and using both sublingual and swallowing, still unusual for me, zonked into mid next day like full dose, Dk who can take this. Tramadol experience similar and disappointing. First few trials, sedation, several moth use, less sedation, pain relief creeps into muscles and tendons, not bad. A year of use, less sedation, no pain relief, burns out mu receptors, requires stopping for x amount of time, restarting. No other options so I get up at 0400 to take it with two acetaminophen, does nothing for first dose, have started taking second dose at 5 1/2 hours later, not six, maybe blood level curve is such it whacks receptors harder so I get a bit of pain relief now, bit better after third dose 5 1/2 hours later, with various bad side effects, constricted throat scary, breathing effect also not cool. Another crummy med for the desperate. Just refused OxyContin, maybe road to ruin based on friends’ usage.sign up for Betty Ford when you start taking it, it appears.

  3. HJ at 7:55 am

    If it had not been a re-formulation of flexeril/cyclobenzaprine, then yes: I would have been upset.

    Cyclobenzaprine is on the market and available as an off-label treatment for fibromyalgia. It is a generic medication, which means a lower copay. The difference, as I understand it: the cyclobenzaprine that’s currently available is a higher dose than what Tonix was testing, and it is not sub-lingual.

    If we lost anything here, we lost an opportunity to be charged brand-name copays for a drug that was already available on the market.

    I do not see a lower dose to be an advantage, in my personal experience. Perhaps the delivery method would make it get into your system faster… but frankly, it seems like asking a pharmacist “How long after I take this medicine does it start to work?” I used to take my cyclobenzaprine a full hour and a half before I was ready for bed. For some people, it may work faster but that was my personal experience.

    Anyone taking a drug and expecting instant relief/response is likely to be disappointed, so even with pain medications, it may help to be aware of how long until it starts to take effect. If you’re not willing to ask a pharmacist, take personal notes about your experience so that you can plan better.

    When I started taking Tramadol, I would feel a little woozy and very talkative about 30-45 minutes after taking the medication. The side-effects were a clue, too. Now that I no longer experience these (my body got used to the tramadol), I do still get pain relief in about 45 minutes after taking the medication. I don’t know how that falls in line with what a pharmacist may tell me but it’s helpful for me to be aware. I actually can plan physical activities around this knowledge — if I know I have a task that will require more of me, I wait until my dose has taken effect. I take tramadol before bed, so I don’t wait to take it until right before bed — I take it 30-45 minutes before bed.

    Doctors probably should clue their patients in about when to take medications for sleep, especially. When I was first given meds for sleep, I thought they’d failed me because they didn’t work 10 minutes after I took them. Trazodone took a full hour and a half for me to really start feeling drowsy. It’s not intiuitive to take sleep meds at 7:30pm when you want to sleep at 9pm.

  4. Bob Schubring at 11:50 pm

    Interesting to get the perspective of someone engaging with the FDA bureaucracy.

    Any doctor who treats fibro patients, could perform these same experiments by off-label prescribing. Flexeril tablets are available in drug stores. A patient or the doctor could break a Flexeril tablet, using a pill splitter, and instruct the patient to hold the piece of a pill under the tongue and allow it to dissolve for 10 minutes, then swallow.

    It would be possible for doctors and patients to do this experiment, without FDA involvement, report the results, study who gets better and who does not, and try to identify differences between patients whom the drug helps, and patients who need a different treatment.

    Some truly dangerous treatments are legal by this off-label route, such as the intrathecal steroid injections that cause arachnoiditis.

    The least our community could do, is apply the off-label prescribing law, to continue studying whether the muscle relaxant Flexeril, given in low dosage, improves the quality of sleep for any fibromyalgia patients.

  5. Rk at 10:50 pm

    Not surprising I stopped taking flexeril months ago because it makes you unable to wake up in the morning and I lost jobs be cause of oversleeping so being forced to work even though I’m disabled I had to stop taking it must he nice to afford to be able to sleep more then 4 hours and not worry about going to work w extreme chronic pain.

  6. Steve at 4:48 pm

    I think this is one of two local trials I passed up because I would have needed to get off other meds. I had also tried the old cyclobenzaprine and thought it was a miserable med, had many doubts it could be revamped. Too bad for study participants, placebo folks and others, probably 13 weeks (if I remember) without meds. We are not in a good spot when Big Pharma (or little pharma here) just revamps very older meds instead of testing new ones for us.

  7. Pamela Hansen at 3:04 pm

    Well if it’s not working then that’s good to go no further but would hope they find a cure or a med that helps us all. Pam

  8. JRL at 8:34 am

    I am disappointed because Cyclobenzaprine helps me at night but I find that it takes extremely long to realize its benefits, approximately two hours.

    The obvious answer would be to take it early and I do but when dealing with acute pain that waxes and wanes, it can be a very long time to wait.

  9. Angel at 7:08 am

    This is not surprising. The over diagnosis of fibro means you have a pool of folks in the trial with various other ailments misdiagnosed as fibro. Fibros growing list of symptoms is leading to a huge increase of misdiagnosis. Until that’s dealt with I doubt any successful treatments will come out as it taints the study pool. This is a shame for those suffering from fibro and those misdiagnosed as well. Neither group will find relief that way. Flexeril is still a viable option and very useful for fibro patients just not in it’s sublingual form.

  10. Angella Anderson at 5:50 am

    I am extremely disappointed with these results, and the company. It sounds to me that they are just looking more at the dollar value because PTSD for our veterans is in the news right now because of the high rate of suicide that they are seeing. It will be approved quickly.
    Can it be prescribed off-label?