Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications

Yves Dauvilliers, Karel Šonka, Richard K Bogan, Markku Partinen, Rafael Del Rio Villegas, Nancy Foldvary-Schaefer, Roman Skowronski, Abby Chen, Jed Black, Franck Skobieranda, Michael J Thorpy, Yves Dauvilliers, Karel Šonka, Richard K Bogan, Markku Partinen, Rafael Del Rio Villegas, Nancy Foldvary-Schaefer, Roman Skowronski, Abby Chen, Jed Black, Franck Skobieranda, Michael J Thorpy

Abstract

Background: Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy.

Objective: The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications.

Methods: Eligible participants (adults aged 18-70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3-10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study.

Results: At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1-2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3-10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics.

Conclusions: LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics.

Trial registration: A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://ichgcp.net/clinical-trials-registry/NCT03030599 ; clinicaltrials.gov identifier: NCT03030599.

Conflict of interest statement

Yves Dauvilliers is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Flamel Technologies, Idorsia, Takeda, Theranexus, and Bioprojet. Karel Šonka has served on the speakers’ bureau for Sanofi, Angelini, and Stada and participated in advisory boards for UCB and in clinical trials for Jazz Pharmaceuticals, Flamel-Avadel, and Luitpold Pharmaceuticals. Richard K. Bogan is a shareholder of WaterMark Medical and Healthy Humming, LLC; is on the board of directors of WaterMark Medical; serves as a consultant to Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, and Oventus; conducts industry-funded research for Avadel Pharmaceuticals, Axsome Therapeutics, Bresotec Medical, Bayer, Idorsia, Suven Life Sciences, Jazz Pharmaceuticals, Balance Pharma Inc., NLS Pharmaceutics, Vanda Pharmaceuticals Inc., Merck, Eisai Co. Ltd, Philips, Fresca Medical, Takeda, LivaNova, Roche, Sanofi, Sommetrics, and Noctrix Health; and has served on the speakers’ bureau for Jazz Pharmaceuticals, Eisai Co. Ltd., and Harmony Biosciences. Markku Partinen has participated in advisory boards of AOP Orphan, Bioprojet, UCB, and Umecrine. He has participated in clinical trials for Bioprojet, Jazz Pharmaceuticals, MSD, and Umecrine. Rafael del Rio Villegas has participated in advisory boards for Bioprojet and trials for Jazz Pharmaceuticals, Bioprojet, and Takeda. Nancy Foldvary-Schaefer served as a consultant for Jazz Pharmaceuticals and receives research support from Jazz Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceuticals. Roman Skowronski is a full-time employee of Jazz Pharmaceuticals who, in the course of this employment, has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals, plc. Abby Chen is a full-time employee of Jazz Pharmaceuticals who, in the course of this employment, has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals, plc. Jed Black is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals plc. Franck Skobieranda is a full-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals, plc. Michael J. Thorpy has received research/grant support and consultancy fees from Jazz Pharmaceuticals, Harmony Biosciences, Balance Therapeutics, Axsome Therapeutics, and Avadel Pharmaceuticals.

© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Figures

Fig. 1
Fig. 1
Study design. DBRWP double-blind randomized withdrawal period, LXB lower-sodium oxybate, OLE open-label extension, OLOTTP open-label optimized treatment and titration period, SDP stable-dose period, SFU safety follow-up, SXB sodium oxybate
Fig. 2
Fig. 2
Distribution of cataplexy frequency during week 1, by treatment at study entry (safety population). n numbers of participants with available data, SXB sodium oxybate
Fig. 3
Fig. 3
Median weekly cataplexy attack frequency during OLOTTP and SDP, by treatment at study entry (efficacy population). Linear regression fitting of median data was used to estimate trends in cataplexy frequency changes; p-values associated with slopes are based on t tests. p-values are nominal. OLOTTP open-label optimized treatment and titration period, SDP stable-dose period, SE standard error, SXB sodium oxybate
Fig. 4
Fig. 4
Median cataplexy-free days per week during OLOTTP and SDP, by treatment at study entry, and during DBRWP, by randomized treatment (efficacy population). Slope is from week 1 to week 14. Linear regression fitting of median data was used to estimate trends in cataplexy frequency changes; p-values associated with slopes are based on t tests. p-values are nominal. DBRWP double-blind randomized withdrawal period, LXB lower-sodium oxybate, OLOTTP open-label optimized treatment and titration period, SDP stable-dose period, SE standard error, SXB sodium oxybate

References

    1. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine; 2014.
    1. Kornum BR, Knudsen S, Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, et al. Narcolepsy. Nat Rev Dis Prim. 2017;9(3):16100. doi: 10.1038/nrdp.2016.100.
    1. Maski K, Steinhart E, Williams D, Scammell T, Flygare J, McCleary K, et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J Clin Sleep Med. 2017;13(3):419–425. doi: 10.5664/jcsm.6494.
    1. Dauvilliers Y, Siegel JM, Lopez R, Torontali ZA, Peever JH. Cataplexy–clinical aspects, pathophysiology and management strategy. Nat Rev Neurol. 2014;10(7):386–395. doi: 10.1038/nrneurol.2014.97.
    1. Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705–1711. doi: 10.1093/sleep/30.12.1705.
    1. Swick TJ. Treatment paradigms for cataplexy in narcolepsy: past, present, and future. Nat Sci Sleep. 2015;7:159–169.
    1. Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF. Treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1712–1727. doi: 10.1093/sleep/30.12.1712.
    1. Lopez R, Arnulf I, Drouot X, Lecendreux M, Dauvilliers Y. French consensus. Management of patients with hypersomnia: which strategy? Rev Neurol (Paris). 2017;173(1–2):8–18. doi: 10.1016/j.neurol.2016.09.018.
    1. Billiard M, Bassetti C, Dauvilliers Y, Dolenc-Groselj L, Lammers GJ, Mayer G, et al. EFNS guidelines on management of narcolepsy. Eur J Neurol. 2006;13(10):1035–1048. doi: 10.1111/j.1468-1331.2006.01473.x.
    1. Ristanovic RK, Liang H, Hornfeldt CS, Lai C. Exacerbation of cataplexy following gradual withdrawal of antidepressants: manifestation of probable protracted rebound cataplexy. Sleep Med. 2009;10(4):416–421. doi: 10.1016/j.sleep.2008.04.004.
    1. Xyrem® (sodium oxybate) oral solution, CIII [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2020.
    1. Xyrem [summary of product characteristics]. Brussels, Belgium: UCB Pharma; 2021.
    1. Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution, CIII [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2021.
    1. Chen C, Jenkins J, Zomorodi K, Skowronski R. Pharmacokinetics, bioavailability, and bioequivalence of lower-sodium oxybate in healthy participants in 2 open-label, randomized, crossover studies. Clin Transl Sci. 2021;14(6):2278–2287. doi: 10.1111/cts.13087.
    1. Junnarkar G, Allphin C, Profant J, Steininger TL, Chen C, Zomorodi K, et al. Development of a lower-sodium oxybate formulation for the treatment of patients with narcolepsy and idiopathic hypersomnia. Expert Opin Drug Discov. 2022;17(2):109–119. doi: 10.1080/17460441.2022.1999226.
    1. Bogan RK, Thorpy MJ, Dauvilliers Y, Partinen M, Del Rio Villegas R, Foldvary-Schaefer N, et al. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. 2021;44(3):zsaa206.
    1. Lipton RB, Lee L, Saikali NP, Bell J, Cohen JM. Effect of headache-free days on disability, productivity, quality of life, and costs among individuals with migraine. J Manag Care Spec Pharm. 2020;26(10):1344–1352.
    1. Auvin S, Williams B, McMurray R, Kumar D, Perdomo C, Malhotra M. Novel seizure outcomes in patients with Lennox-Gastaut syndrome: Post hoc analysis of seizure-free days in rufinamide Study 303. Epilepsia Open. 2019;4(2):275–280. doi: 10.1002/epi4.12314.
    1. Husain AM, Bujanover S, Ryan R, Scheckner B, Black J, Profant J. Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy. J Clin Sleep Med. 2020;16(9):1469–1474. doi: 10.5664/jcsm.8530.
    1. Baldwin DS, Foong T. Antidepressant drugs and sexual dysfunction. Br J Psychiatry. 2013;202:396–397. doi: 10.1192/bjp.bp.112.110650.
    1. Anafranil [package insert]. Hazelwood, MO: Mallinckrodt Inc.; 2012.
    1. Effexor XR [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017.
    1. Vivactil [package insert]. Horsham, PA: Teva Pharmaceuticals USA, Inc; 2014.
    1. American Psychiatric Association. Treating major depressive disorder: a quick reference guide. 2010 October 2010. Cited 29 October 2021. .
    1. Plazzi G, Strunc MJ, Parvataneni R, Wang G, Black J, Bogan R. Dosing, titration, and treatment compliance to sodium oxybate therapy in pediatric patients with narcolepsy [abstract 0765] Sleep. 2019;42(suppl 1):A307–A308. doi: 10.1093/sleep/zsz067.763.
    1. U.S. Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004;5(2):119–23.
    1. Cohen A, Mandrekar J, St Louis EK, Silber MH, Kotagal S. Comorbidities in a community sample of narcolepsy. Sleep Med. 2018;43:14–18. doi: 10.1016/j.sleep.2017.11.1125.
    1. Black J, Reaven NL, Funk SE, McGaughey K, Ohayon MM, Guilleminault C, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13–18. doi: 10.1016/j.sleep.2016.04.004.
    1. Jennum P, Ibsen R, Knudsen S, Kjellberg J. Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Sleep. 2013;36(6):835–840. doi: 10.5665/sleep.2706.
    1. Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013;14(6):488–492. doi: 10.1016/j.sleep.2013.03.002.
    1. Pepin JL, Borel AL, Tamisier R, Baguet JP, Levy P, Dauvilliers Y. Hypertension and sleep: overview of a tight relationship. Sleep Med Rev. 2014;18(6):509–519. doi: 10.1016/j.smrv.2014.03.003.
    1. Jennum PJ, Plazzi G, Silvani A, Surkin LA, Dauvilliers Y. Cardiovascular disorders in narcolepsy: review of associations and determinants. Sleep Med Rev. 2021;58:101440. doi: 10.1016/j.smrv.2021.101440.
    1. Perrin G, Korb-Savoldelli V, Karras A, Danchin N, Durieux P, Sabatier B. Cardiovascular risk associated with high sodium-containing drugs: a systematic review. PLoS ONE. 2017;12(7):e0180634. doi: 10.1371/journal.pone.0180634.
    1. Wei L, Mackenzie IS, MacDonald TM, George J. Cardiovascular risk associated with sodium-containing medicines. Expert Opin Drug Saf. 2014;13(11):1515–1523. doi: 10.1517/14740338.2014.970163.
    1. Clinical superiority findings. 2021. . Cited 9 July 2021.

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