Efficacy and Safety of ASP0819 in Patients with Fibromyalgia: Results of a Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial
Leslie M Arnold, Mary Beth Blauwet, Katherine Tracy, Na Cai, Mark Walzer, Paul Blahunka, Gerard J Marek, Leslie M Arnold, Mary Beth Blauwet, Katherine Tracy, Na Cai, Mark Walzer, Paul Blahunka, Gerard J Marek
Abstract
Purpose: ASP0819 is a novel, non-opioid KCa3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects.
Patients and methods: In this phase 2a, double-blind trial (NCT03056690), adults meeting fibromyalgia diagnostic criteria were randomized 1:1 to receive either 15 mg/day of oral ASP0819 (n=91) or placebo (n=95). The primary endpoint was the change from baseline to Week 8 in the mean daily average pain score. Changes in the Fibromyalgia Impact Questionnaire Revised (FIQR) symptoms, function, and overall impact subscales, as well as changes in the patients' global impression of change, were secondary endpoints; treatment effects on FIQR total score and impact on sleep were exploratory analyses.
Results: There was no statistically significant difference between ASP0819 and placebo for the primary endpoint (P=0.086); however, ASP0819 versus placebo significantly improved daily average pain at Weeks 2, 6, and 7 (all P<0.05). Numerical improvements were observed on the FIQR total score and several sleep items showed statistically significant improvements with ASP0819 versus placebo. There were no major safety concerns with ASP0819. Headache was the most common treatment-emergent adverse event (TEAE) occurring in both study arms; most TEAEs were mild or moderate in severity and no TEAEs suggestive of potential drug abuse were observed, as assessed by TEAE reporting and/or safety evaluations. Withdrawal effects also were not observed.
Conclusion: ASP0819 demonstrated some signals suggestive of efficacy and had a good tolerability profile in patients with fibromyalgia. Further studies are required to determine if ASP0819 can be a novel non-opioid treatment option in this patient group.
Clinicaltrialsgov registration: NCT03056690.
Keywords: ASP0819; clinical trial; fibromyalgia; non-opioid treatment; pain.
Conflict of interest statement
L. Arnold has consulted for Pfizer, Eli Lilly, Astellas, Teva, Allergan, Daiichi Sankyo, Jazz Pharmaceuticals, Zynerba, Prismic, Cinrx, Innovative Med Concepts, and Lundbeck and has received research support from Pfizer, Eli Lilly, Daiichi Sankyo, Axsome, Tonix, Allergan, Aptinyx, Teva, Astellas, and Cefaly; and reports grants and personal fees from Astellas, during the conduct of the study; personal fees from Pfizer, Eli Lilly, Teva, Allergan, Daiichi Sankyo, Jazz Pharmaceuticals, Zynerba, Prismic, Cinrx, Innovative Med Concepts, and Lundbeck, and grants from Pfizer, Eli Lilly, Daiichi Sankyo, Axsome, Tonix, Allergan, Aptinyx, Teva, and Cefaly, outside the submitted work. Mark Walzer and Paul Blahunka have a patent pending: Methods of treating sleep disorders associated with pain (PCT2020/043047). K. Tracy and P. Blahunka are former employees of Astellas. All other authors are current employees of Astellas Pharma Global Development. The authors report no other potential conflicts of interest for this work.
© 2020 Arnold et al.
Figures
References
- Collins FS, Koroshetz WJ, Volkow ND. Helping to end addiction over the long-term: the research plan for the NIH HEAL initiative. JAMA. 2018;320(2):129–130. doi:10.1001/jama.2018.8826
- Volkow ND, Collins FS. The role of science in addressing the opioid crisis. N Engl J Med. 2017;377(4):391–394. doi:10.1056/NEJMsr1706626
- NIH. Improving opioid prescribing: opioid prescribers can play a key role in stopping the opioid overdose epidemic. Published 2017. Available from: . Accessed January14, 2019.
- Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep. 2013;17(8):356. doi:10.1007/s11916-013-0356-5
- Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010;62(5):600–610. doi:10.1002/acr.20140
- Wolfe F, Clauw DJ, Fitzcharles M-A, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia. J Rheumatol. 2011;38(6):1113–1122. doi:10.3899/jrheum.100594
- Wolfe F, Smythe HA, Yunus MB, et al. The American college of rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum. 1990;33(2):160–172. doi:10.1002/art.1780330203
- 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. doi:10.1016/j.mayocp.2012.02.010
- Azadfard M, Huecker MR, Leaming JM. Opioid Addiction. Treasure Island, FL: StatPearls; 2020.
- Arnold LM, Bennett RM, Crofford LJ, et al. AAPT diagnostic criteria for fibromyalgia. J Pain. 2019;20:611–628.
- Staud R. Brain imaging in fibromyalgia syndrome. Clin Exp Rheumatol. 2011;29(6 Suppl 69):S109–117.
- Serra J, Collado A, Sola R, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol. 2014;75(2):196–208. doi:10.1002/ana.24065
- Staud R, Smitherman ML. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr Pain Headache Rep. 2002;6(4):259–266. doi:10.1007/s11916-002-0046-1
- Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristic electron microscopic findings in the skin of patients with fibromyalgia: preliminary study. Clin Rheumatol. 2008;27(2):219–223. doi:10.1007/s10067-007-0739-2
- Swiecka M, Maslinska M, Kwiatkowska B. Small fiber neuropathy as a part of fibromyalgia or a separate diagnosis? Int J Clin Rheumatol. 2018;13:353.
- Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310–2316. doi:10.1016/j.pain.2013.06.001
- Üçeyler N, Sommer C, Walitt B, Häuser W. Anticonvulsants for fibromyalgia. Cochrane Database Syst Rev. 2013;10.
- Boettger MK, Till S, Chen MX, et al. Calcium-activated potassium channel SK1- and IK1-like immunoreactivity in injured human sensory neurones and its regulation by neurotrophic factors. Brain. 2002;125(Pt 2):252–263. doi:10.1093/brain/awf026
- Hogan Q, Lirk P, Poroli M, et al. Restoration of calcium influx corrects membrane hyperexcitability in injured rat dorsal root ganglion neurons. Anesth Analg. 2008;107(3):1045–1051. doi:10.1213/ane.0b013e31817bd1f0
- Lu R, Flauaus C, Kennel L, et al. KCa3.1 channels modulate the processing of noxious chemical stimuli in mice. Neuropharmacology. 2017;125:386–395. doi:10.1016/j.neuropharm.2017.08.021
- Mongan LC, Hill MJ, Chen MX, et al. The distribution of small and intermediate conductance calcium-activated potassium channels in the rat sensory nervous system. Neuroscience. 2005;131(1):161–175. doi:10.1016/j.neuroscience.2004.09.062
- Wulff H, Kolski-Andreaco A, Sankaranarayanan A, Sabatier JM, Shakkottai V. Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications. Curr Med Chem. 2007;14(13):1437–1457. doi:10.2174/092986707780831186
- Tsantoulas C, McMahon SB. Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci. 2014;37(3):146–158. doi:10.1016/j.tins.2013.12.002
- Khasar SG, Miao JP, Janig W, Levine JD. Modulation of bradykinin-induced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents. Eur J Neurosci. 1998;10(2):435–444. doi:10.1046/j.1460-9568.1998.00030.x
- Takeshita N, Oe T, Kiso T, Kakimoto S. A KCa3.1 channel opener, ASP0819, modulates nociceptive signal processing from peripheral nerves in fibromyalgia. J Pain Res. 2020.
- Nagakura Y, Oe T, Aoki T, Matsuoka N. Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: a putative animal model of fibromyalgia. Pain. 2009;146(1–2):26–33. doi:10.1016/j.pain.2009.05.024
- Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL. The revised fibromyalgia impact questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther. 2009;11(4):R120. doi:10.1186/ar2783
- Rampakakis E, Ste-Marie PA, Sampalis JS, Karellis A, Shir Y, Fitzcharles MA. Real-life assessment of the validity of patient global impression of change in fibromyalgia. RMD Open. 2015;1(1):e000146. doi:10.1136/rmdopen-2015-000146
- Kleinman L, Mannix S, Arnold LM, et al. Assessment of sleep in patients with fibromyalgia: qualitative development of the fibromyalgia sleep diary. Health Qual Life Outcomes. 2014;12:111. doi:10.1186/s12955-014-0111-6
- Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS). New York: The Research Foundation for Mental Hygiene; 2009.
- Poquet N, Lin C. The brief pain inventory (BPI). J Physiother. 2016;62(1):52. doi:10.1016/j.jphys.2015.07.001
- Cetin B, Sunbul EA, Toktas H, Karaca M, Ulutas O, Gulec H. Comparison of sleep structure in patients with fibromyalgia and healthy controls. Sleep Breath. 2020:1–8.
- Türkoğlu G, Selvi Y. The relationship between chronotype, sleep disturbance, severity of fibromyalgia, and quality of life in patients with fibromyalgia. Chronobiol Int. 2020;37(1):68–81. doi:10.1080/07420528.2019.1684314
- Theadom A, Cropley M, Humphrey KL. Exploring the role of sleep and coping in quality of life in fibromyalgia. J Psychosom Res. 2007;62(2):145–151. doi:10.1016/j.jpsychores.2006.09.013
- Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9(9):792–805. doi:10.1016/j.jpain.2008.03.013
- Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol. 2008;35(3):502–514.
Source: PubMed