Health Rising’s Sleep Series 

  • Pt. I Dr. Bruck Interview – Bronc kicked the series off with an interview of Dr. Bruck – a retired sleep researcher whose son has ME/CFS.
  • Pt. IIRuhoy and Kaufman on Sleep – an overview of a fascinating talk by two long-term ME/CFS/FM and chronic illness experts: Dr. David Kaufman and Dr. Illene Ruhoy on sleep  on their Unraveled Patreon podcast.
  • Pt. IIIA new sleep drug for fibromyalgia? A look at Tomnya – a sleep/pain drug Tonix Pharmaceuticals is submitting for FDA approval.
  • Pt. IV –  an interview with Dr. Mullington, a long-time sleep researcher and ME/CFS expert who, courtesy of the Open Medicine Foundation, is using cutting-edge technology to further understand sleep in ME/CFS.


Geoff narrates The GIST

Geoff narrates the blog

There’s Got to Be a Better Way…

People with chronic fatigue syndrome (ME/CFS) can look at fibromyalgia and its three FDA-approved drugs (Lyrica (Pregabalin) – 2007), Cymbalta (Duloxetine) – 2008, and Savella (Milnacipran) – 2009) over 3 years in the US with envy. The truth is, though, these drugs don’t work very well in many people – we’re not missing much.

Will Tonix's Tomnya breakthrough?

Tonix is taking a new approach to fibromyalgia (and ME/CFS). Will it succeed where others have failed?

A 2020 review, “Current and Emerging Pharmacotherapy for Fibromyalgia“, stated:

“it must be acknowledged that pharmacological treatment has been met, in general, with rather modest rates of success in this area.”

That was polite researcher-speak for, “It’s amazing how ineffective these drugs are”. A few paragraphs later, they changed that “modest” to “strikingly modest”.

“The strikingly modest progress in this field, as manifested by the surprisingly low compliance of patients,”


  • Check out the blog for Geoff’s narration of the GIST and the blog 🙂
  • The FDA approved 3 drugs in 3 years (Lyrica (Pregabalin) – 2007), Cymbalta (Duloxetine) – 2008, and Savella (Milnacipran) – 2009) to treat fibromyalgia in the U.S. but studies have shown that most people receive modest benefits from them and don’t stick with them.
  • Bringing a drug to market is a tough business. In the past five years or so at least 4 promising drugs (Mirogabalin, Brincidofovir, Synergy, Rituximab) have failed in large-scale studies.
  •  Tonix’s Tonmya drug – which is heading to the FDA in the second half of this year is an updated version of Flexeril a central nervous system-acting drug that relaxes the muscles.
  • Tonmya’s new sublingual format shoots the drug straight into the body, allowing a significant reduction in the dose, and bypassing the toxicity problems that were relegating Flexeril to short-term use.
  • Tonix is attempting to kill two birds with one stone. By calming the nervous system down during sleep, it hopes to reduce pain and fatigue, etc.
  • Unlike other hypnotic sleep drugs, Tomnya doesn’t help with insomnia. Instead, it produces deeper, more refreshing sleep by reducing the activity of nervous system pathways associated with alertness and vigilance during sleep.
  • Tonix seemed like it had a sure bet but its 2019 fibromyalgia trial failed. The company recalibrated and using a higher dose started two large new fibromyalgia trials – only to suspend one after an interim analysis indicated that it was failing as well.
  • After an analysis indicated that the pandemic had interfered with the results and after the success of a post-pandemic trial Tonix gave it another go – and launched one last large trial. You can’t say this company doesn’t have faith in its drug!
  • That trial was a success. The drug met its primary (reduction in pain) and secondary endpoints (reductions in fatigue, and improvements in sleep) and had an excellent safety profile.
  • Tonix believes that with this drug FM patients can have their cake and eat it too. Instead of trading reductions in pain for fatigue (Lyrica) or worse sleep (Cymbalta), they believe that Tonmya will improve both sleep and pain without the side effects seen with these other drugs.
  • The company will ask for FDA approval in the second half of this year and expects an answer in the second half of next year. If approval is granted fibromyalgia will have its first new FDA-approved drug in 15 years. Time will tell! Check out a video on the blog for FM researcher Daniel Clauw’s thoughts on the drug.

It got even worse:

“Real-life data published over recent years [3], together with the clinical experience of physicians dealing with this group of patients, all indicate that only a minority of fibromyalgia patients continue taking medications for more than a short period of time due to either lack of efficacy, side effects, or both.”

The “strikingly modest” progress may not have been surprising. These weren’t, after all, the most creative drugs in the world: one (Lyrica) was an improved version of Gabapentin while the others were antidepressants (SNRIs).  Fibromyalgia and the chronic pain field need a new approach – and in Tonix’s Tomnya drug, they have it.

Getting a drug approved by the FDA is not easy. The examples below will show the numerous and even worse – unanticipated – ways a drug can fail.

Missed Opportunities

Daichii’s Dumpster Fire

Still, drug companies must have been licking their chops at the spate of FDA-approved drugs that occurred in the late 2000s. After 2009, though, the party was over. Despite several attempts, including the notorious Daichii-Sankyo fiasco, no drugs have been FDA-approved for fibromyalgia in the U.S. in 15 years.

Daichii-Sankyo was so confident in their upgraded version of Lyrica called Mirogabalin that it went straight to a huge Phase III trial (3,600 patients in 300 centers worldwide) without doing any Phase II safety and efficacy trials.

It was easy to understand their confidence. Mirogabalin was supposed to be Lyrica without the side effects, but the drug utterly bombed. In two unusual reports, the company argued both before and after the trial that the new outcome measures the FDA had put in place for FM made it more difficult for drugs to be approved.

*See “Did the FDA Mess Up the Biggest Fibromyalgia Trial Ever?

Bye-bye Brindcifovir

Some people may remember CMX-001 or Brindcifovir – the next great antiherpesvirus drug. Studies suggested that this Vistide upgrade was effective against many types of viruses, leading the FDA to give it fast-track status for no less than three separate viruses.

Brindcifovir sailed through large Phase 2 trials but then stunk it up in its Phase 3 trial (perhaps because of something the doctors unwittingly did). Subsequently, Chimerix, its manufacturer, halted two more phase 3 trials and ultimately sold the drug to another company.

Sorry Synergy

Over in ME/CFS, the phase II Synergy trial combining methylphenidate and mitochondrial nutrients seemed to be a lock before it, too, failed to meet its primary endpoint. The unusually high placebo effects may have doomed it. (It did well in a Gulf War Illness study.)

Stimulating Energy: Enhancing the Mitochondria in the Synergy Clinical Trial for Chronic Fatigue Syndrome

The Big Hurt – Rituximab Bombs

The one that really hurt, though, was Rituximab which aced early trials only to bomb in its Phase III trial for ME/CFXS. (One ME/CFS researcher believes a reduced maintenance dose may have been the culprit.)

Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails

There are clearly many ways for a drug – even potentially a good drug – to fail.

A Better Way? 

Health Rising has been following Tonix Pharmaceutical’s Tonmya (formerly TNX-102) story with fascination and, at times, horror for about five years. Tonix has been anything but exempt from the pitfalls that drug companies can experience. The notable thing about this small drug company has been its persistence.  It’s been like the little engine that could: through thick and thin it’s just kept pulling this drug up the mountain.

An updated form of Flexeril (cyclobenzaprine), TNX-102, or Tonmya charted a new path. Tonmya is a muscle relaxant that relaxes muscles via the central nervous system. Its new sublingual format shoots the drug straight into the body, allowing a significant reduction in the dose, and bypassing the toxicity problems that were relegating Flexeril to short-term use. By reducing the activity of nervous system pathways associated with alertness and vigilance during sleep – and thereby relieving pain as well, Tonix aimed Tonmya at key areas of FM and ME/CFS.

It seemed that more refreshing sleep AND reduced pain might be on their way for FM patients, but the 2019 trial failed. Its interest in FM apparently over, Tonix reported that it would try again with PTSD. When its PTSD trial trial succeeded with a larger dose, though, Tonix thought it had its answer.

Reinvigorated, the company started two new, large, Phase III FM trials (RELIEF, RALLY) using the higher dose. After an interim analysis suggested the drug would not make its primary endpoints, Tonix abruptly suspended the RALLY mid-trial. Tonmya was, once again, on the rocks.

Further analyses suggested that Tonix had found a new way to fail a treatment trial. While it’s analyses suggested the RALLY trial successfully reduced pain levels, the high dropout rates occurring during the pandemic on both arms of the trial (TNX-12, placebo) scotched the kind of analysis the FDA required.

Tonix’s successful RELIEF trial, which began after the pandemic, convinced Tonix that despite two expensive trial failures, it was on the right track. The little drug company that seemed never willing to say no started its aptly named RESILIENT phase III trial. No one can say Tonix hasn’t had faith in its drug.

Tonix Launches Decisive Fibromyalgia Treatment Trial Plus Big Year for Fibromyalgia Drugs?

Resilient Indeed

The results of the 457-person trial are in. Tonix reported that this time the drug met its pre-specified primary endpoint by significantly reducing daily pain compared to placebo (p=0.00005). Tonix reported that clinically meaningful results were also seen in all major secondary endpoints related to improving sleep quality, reducing fatigue, and improving overall fibromyalgia symptoms and function. Almost 50% of FM patients taking the drug reported at least a 30% decline in pain. The drug worked quickly as well and started to have an effect in the first week of use. Its effect size of .38 is considered a “moderate” effect size.

Abbreviations: LS = least squares; NRS = numerical rating scale; SE = standard error.

Daniel J. Clauw, M.D., a well-known fibromyalgia researcher and Director of the Chronic Pain and Fatigue Research Center at the University of Michigan, called the results “terrific news for patients with fibromyalgia”. He noted that the drug’s active ingredient has a “known, favorable safety profile from decades of use” and that it was beneficial “in many other key symptom domains, including sleep quality, sleep disturbance, and fatigue”. (See Dr. Clauw and another long-time FM researcher Leslie Arnold in the below webinar.)

Tomnya also appears to be quite safe, with the most common systemic side effects –  headache and somnolence – occurring in about 3% of patients. No weight gain, as occurs with Lyrica or antidepressants, was found.

Indeed, Tonix believes its drug is unique in fibromyalgia pharmacology because it doesn’t present any tradeoffs. People who take Lyrica to reduce their pain often have less energy. Likewise, people who take Cymbala or Savella often experience worse sleep. They believe Tonmya can improve pain, sleep, and fatigue.

The Sleep Angle

For Tonix, sleep is where it’s at. Seth Lederman, Tonix’s president referred me to Dr. Iredell Iglehart III’s 2003 patent which described a drug that reduced pain in fibromyalgia (as well as ME/CFS) by improving sleep. The novel part of Iglehart’s patent was that a low dose of cyclobenzaprine (or a metabolite of cyclobenzaprine) was required.

The goal for Tonix is not to produce longer sleep nor to prevent insomnia but to produce deeper, more refreshing sleep. It believes that non-restorative sleep may be the Achilles heel of FM and ME/CFS. Moldovsky’s pioneering Toronto studies in the 90s, and others since then, have indicated that poor sleep increases pain sensitivity.

In 1993, Moldovsky reported that “chronic fatigue syndrome and fibromyalgia have similar disordered sleep physiology, namely an alpha rhythm disturbance (7.5-11 Hz) in the electroencephalogram (EEG) within non-rapid eye movement (NREM) sleep that accompanies increased nocturnal vigilance and light, unrefreshing sleep.” It’s the “nocturnal vigilance” and light, unrefreshing sleep that sets diseases like ME/CFS and FM apart. More recent research calls this a “hyperarousal sleep disorder”.

Tonmya is different from other sleep drugs in that it blocks 4 receptors associated with increased alertness. It’s notable that the hypnotic sleep drug Ambien, which does increase sleep times but does not affect deep sleep, did not improve pain levels in FM.

Is a Hyperarousal Sleep Disorder Keeping People with Fibromyalgia and ME/CFS Up at Night

Tonix proposes that the brains of FM and ME/CFS patients are simply too alert. Indeed, several studies suggest that the sympathetic nervous system (fight/flight) activation and sleep fragmentation play a key role in these diseases. It may not be so much that ME/CFS/FM patients are not getting enough deep sleep but that their deep sleep is not deep enough. A 2020 Australian ME/CFS sleep study concluded:

“Autonomic hypervigilance during the deeper, recuperative stages of sleep is associated with poor quality sleep and self-reported wellbeing.”

In short, ME/CFS/FM in several ways, seems tailor-made for a drug that can help the brain to calm down and rest during sleep. That’s what Xyrem (sodium oxybate) – the sleep drug that came close to being approved by the FDA for sleep – does. Xyrem was rejected, not because it didn’t work in FM, but because of its use as a date rape drug.


Tonix plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the second half of 2024 for Tonmya. Lederman told me it’s taken 700 hundred million dollars (!) in funding to get this far, but Tonix and we should know by the second half of next year if fibromyalgia finally has a new FDA-approved drug. If Tonmya is approved, it could hit the market 3 months later. Time will tell!

Found This Blog Helpful? Please Support Health Rising and Keep the Information Flowing





Like the blog you're reading? Don't miss another one.

Get the most in-depth information available on the latest ME/CFS and FM treatment and research findings by registering for Health Rising's free  ME/CFS and Fibromyalgia blog here.

Stay on Top of the News!

Subscribe To Health Rising’s Free Information on Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM), Long COVID and Related Diseases.

Thank you for signing up!

Pin It on Pinterest

Share This