Tonix Pharmaceuticals is enrolling participants in a Phase 3 trial for fibromyalgia, the RALLY study.
For more information, please visit www.RALLYStudy.com or www.clinicaltrials.gov (NCT04508621).

Therapeutic Areas
: Fibromyalgia

Fibromyalgia

What is fibromyalgia (FM)?

FM is one of the more common chronic pain disorders frequently associated with comorbid conditions including fatigue and nonrestorative sleep (Arnold, 2012; Chinn 2016). It is considered a neurobiological disorder in that research has shown that changes in the central nervous system results in alternations in the processing of pain signals, such that the perception of pain becomes amplified. Thus, patients with FM have a lower pain threshold, and perceive pain with a lower level of stimuli. This abnormal central processing of pain in FM is referred to as central sensitization (Chinn, 2016). Symptoms associated with FM in addition to chronic pain include non-restorative sleep, fatigue and morning stiffness. Other associated symptoms include cognitive dysfunction and mood disturbances, including anxiety and depression. As a result, individuals suffering from fibromyalgia struggle with their daily activities, have impaired quality of life, and frequently are disabled.

Sleep disturbances are extremely prevalent in FM, with many studies reporting abnormalities in over 90% of individuals (Chinn, 2016). The current understanding is that pain and abnormal sleep occur in cycles, with the severity of pain correlated with the severity of sleep disturbances. These sleep disturbances include frequent awakenings, non-refreshing sleep, nocturnal restlessness and daytime somnolence.

FM is not an inflammatory or autoimmune disease, although historically it has been associated with rheumatic disorders. As other rheumatic conditions result in chronic joint and muscle pain, a rheumatologist often must differentiate FM from these other disorders, and thus rheumatologists play an important role in the initial diagnosis and selection of a treatment plan for FM.

How prevalent is FM?

FM is a global problem, with prevalence estimated to be 2 to 4 percent of the world population (Hauser 2015). In the U.S., the prevalence has been estimated to also be 2-4% (American College of Rheumatology), while in Europe, the estimate is 2.9% (Branco, 2010 ). As such, FM is the second most common rheumatological disorder, second only to osteoarthritis (Chinn, 2016).

The diagnosed population for FM in the U.S. has been estimated to be 1.1% of the adult population, representing approximately 2.75 million individuals (Vincent, 2013). Approximately 85% (~2.34 million) of those diagnosed with FM will receive treatment (Robinson, 2012).

What are the current treatments for FM and what are their limitations?

Current treatments for FM include both non-pharmacological and pharmacological options (Chinn, 2016). Non-pharmacological treatments include exercise, ‘mind and body’ therapy, as well as acupuncture and massage therapy.

Among the pharmacological treatments, the most commonly used are tricyclic antidepressants (TCA), muscle relaxants, serotonin norepinephrine reuptake inhibitors (SNRIs), and anti-epileptic drugs (AEDs). In the U.S., only three drugs have been approved for the treatment of FM; pregabalin (an AEDs), and duloxetine and milnacipran (SNRIs). All other drugs used to treat FM are used off-label. In Europe, there are no approved drug therapies for the treatment of FM.

Pregabalin has been shown to be effective in several randomized clinical trials (Bhusal, 2016). Clinically meaningful reductions in pain have been demonstrated, however only 42-50% of patients will experience a >30% reduction in pain, and 24-30% will experience >50% reduction in pain, with some studies reporting even lower response rates. In addition, common side-effects include dizziness (40-50%) and somnolence (30-45%), which can lead to discontinuation (dizziness 3-9%; somnolence 3-6%). Weight gain has also been reported, with 10% of patients reporting a significant increase in weight (>7% weight gain), leading to discontinuation in 2% of patients.

Duloxetine, milnacipran, desvenlafaxine, all SNRIs, have been extensively studied in clinical trials as a treatment for FM, and a meta-analysis aggregating the results from these trials has been conducted (Welsch, 2018). Combined results for duloxetine, milnacipran and desvenlafaxine showed that the SNRIs had a >30% reduction in pain in 40% of individuals and >50% reduction in pain in 31% of individuals. Withdrawals from the studies due to lack of efficacy was 7%. Most frequent adverse events were nausea (32%), somnolence (11%), insomnia (10%), collectively resulting in a dropout rate of 19% due to adverse events. In addition, there was no reduction in sleep disturbances relative to placebo.

Overall, the clinical trial evidence for AEDs and SNRIs show that while these therapies can be effective, many patients do not fully respond to treatment, and/or discontinue therapy due to adverse events.

Real world data provides further evidence that many FM patients are not well served by existing treatments. First, there is a high degree of medication augmentation with the average patient using 2.6 medications simultaneously and 24% taking an opioid (Robinson, 2012). Second, switching medications is common, with the average patients having tried over 6 different medications (Patient Trends FM Decision Resources, 2011). This treatment patterns of high augmentation and switching is indicative of patient populations not receiving an adequate response or not tolerating existing medications.

The unmet need in FM includes safe and effective therapies working through unique mechanisms of action for those patients who experience an incomplete efficacy response and/or who cannot tolerate existing medications.

To learn about TNX-102 SL for FM

  1. Arnold LM, Clauw DJ, Dunegan LJ, Turk DC, A Framework for Fibromyalgia Management for Primary Care Providers. Mayo Clin Proc 2012; 87(5):488-496.
  2. Chinn S, Caldwell W, Gritsenko K, Fibromyalgia pathogenesis and treatment options update. Curr Pain Headache Rep 2016; 20:25-34
  3. Häuser W, Ablin J, Fitzcharles MA, Littlejohn G, Luciano JV, Usui C, Walitt B. Fibromyalgia. Nat Rev Dis Primer 2015; 1:15022.
  4. American College of Rheumatology (www.ACRPatientInfo.org accessed May 7, 2019) – prevalence rate of 2-4% for U.S. adult population (~250 million)
  5. Vincent A, Lahr BD, Wolfe F, Clauw DJ, Whipple MO, Oh TH, Barton DL, St Sauver J. Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis Care Res (Hoboken). 2013;65(5):786-92.
  6. Branco JC, Bannwarth B, Failde I, Carbonell JA, Blotman F, Spaeth M, Saraiva F, Nacci F, Thomas E, Caubère J, Lay KL, Taieb C, Matucci-Cerinic M, Prevalence of fibromyalgia: a survey in five European countries. Semin Arthritis Rheum. 2010;39(6):448-453.
  7. Bhusal S, Diomampo S, Magrey MN, Clinnical utility, safety and efficacy of pregabalin in the treatment of fibromyalgia, Drug, Healthcare and Patient Safety 2016; 8:13-23.
  8. Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD010292
  9. Robinson RL. Kroenke K, Mease P, Williams DA, Chen, Y, D’Souza D, Wohlreich, M, McCarberg, B. Burden of illness and treatment patters for patients with fibromyalgia. Pain Medicne, 2012; 13:1366-1376.
  10. Patient trends in FM, Decision Resources, 2011