Botulinum Toxin in Cervical Dystonia

NeurologyLiveAugust 2023
Volume 6
Issue 4

Cervical dystonia, the most common form of focal dystonia, has shown to be able to be effectively managed with a variety of botulinum toxin formulations.

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Kevin Chang, PharmD

Kevin Chang, PharmD

CERVICAL DYSTONIA (CD), also known as spasmodic torticollis, is the most common form of focal dystonia characterized by involuntary contractions of the muscles in the neck region.1 These contractions lead to abnormal head and neck movements, often presenting as a combination of collis (abnormal forward flexion) and caput (twisting or tilting of the head).1 CD is most commonly seen in patients older than 40 years, with a mean prevalence of approximately 4.98 of every 100,000 people,1 although some estimates show a higher prevalence of 5.7 to 400 per 100,000 people.2

In addition to experiencing motor symptoms, patients with CD frequently experience nonmotor symptoms that contribute to the overall disease burden.3 Neuropsychiatric disorders such as depression, anxiety, and sleep-related disorders are more commonly observed in individuals with CD than the general population, further affecting their quality of life.1 Improvement in neuropsychiatric symptoms may also be independent of motor symptom improvement, which may indicate that neuropsychiatric disorders are not secondary to CD.1,3

Botulinum toxin (BoNT) injections are the recommended therapeutic intervention for CD by the American Academy of Neurology.4 There are 8 serotypes of BoNT from A to H, with 3 formulations of serotype A (onabotulinumtoxinA [Botox], abobotulinumtoxinA [Dysport], and incobotulinumtoxinA [Xeomin]), and 1 formulation of serotype B (rimabotulinumtoxinB [Myobloc]) in clinical use.5 BoNT has demonstrated favorable efficacy and minimal adverse effects and serves as the mainstay of treatment for CD.1,4

BoNT acts on the presynaptic neurons that normally release acetylcholine (ACh) at the presynaptic terminal by disrupting the SNARE (soluble N-ethylmaleimide–sensitive factor attachment receptor) protein complex, which is necessary for vesicle fusion during muscle contraction.2,6 The SNARE protein complex is essential for the release of neurotransmitters, including ACh, at the neuromuscular junction, which leads to muscle contraction (FIGURE).6,7

Disruption of the SNARE complex by BoNT interferes with ACh release, thereby preventing contraction of agonist and antagonist muscles.2 This temporary muscle paralysis induced by BoNT can be therapeutically beneficial in conditions such as CD and other movement disorders.2 The proposed mechanism of action for periodic BoNT administrations is thought to be from the formation of axonal sprouts, although this mechanism has been challenged.2,5

(Click to enlarge)

(Click to enlarge)

Despite BoNT being the most strongly recommended therapy for CD,4 approximately 30% of patients discontinue treatment because of ineffective symptom reduction or significant adverse effects.1 Because BoNT formulations are derived from a bacterial source, the development of neutralizing antibodies (NABs) is a concern; immunogenicity has been linked to clinical secondary nonresponsiveness.8 Factors that may increase resistance to treatment include shorter intervals between injections, larger individual and cumulative doses, and high protein load.1,7,8 Current BoNT formulations have been recommended and integrated into package inserts to follow a minimum 12-week interval between sessions to reduce the risk of NAB formation.7 However, because of these longer interinjection intervals, patients may experience periods of decreased efficacy as the effect of the injections begins to wear off prior to the next dose.7,9 Higher doses in CD compared with other movement disorders also present a direct correlation between dose and presence of NABs.7 In the ongoing development of new BoNT formulations, there is a focus on the protein load, which indicates a connection to immunogenicity and potential secondary nonresponsiveness.7,8 Protein load is the total amount of proteins in a BoNT formulation, which consists of the core neurotoxin and nontoxic accessory proteins (NAPs).7 NAPs have a nontherapeutic role but may have immunologic response that could lead to NAB formation, increasing the risk of clinical nonresponsiveness.7,8 Samadzadeh et al compared the protein-free incobotulinumtoxinA against both abobotulinumtoxinA and onabotulinumtoxinA, and found that higher protein load correlated with higher prevalence of NAB induction, and recommended starting with a lower protein load preparation.10

DaxibotulinumtoxinA (Daxxify; DAXI) is a new formulation of botulinumtoxinA for injection under clinical review for the treatment of CD.11,12 DAXI is distinguished by its use of a novel peptide, RTP004, as a stabilizing excipient with the core neurotoxin to prevent self-aggregation of the product. This departure from the use of human serum albumin, the excipient found in all other BoNTs on the market, gives DAXI a unique edge.11 Using RTP004 allows DAXI to remain stable at room temperature for up to 3 years in lyophilized form.11 After being reconstituted, DAXI is stable for 72 hours at 2 °C to 8 °C.11 This is an improvement over the shelf life of current BoNT alternatives, most of which require refrigeration when unreconstituted and must be used within 24 to 36 hours once reconstituted.11 Its cationic peptide also provides DAXI with increased affinity for the anionic presynaptic membrane, which may increase the degree of BoNT internalization; this is the hypothesized mechanism underlying this agent’s longer duration of effect.11

In a phase 2, open-label, dose-escalation study (NCT02706795), DAXI was found to achieve a mean duration of response (DOR) of 25.3 weeks, with DOR defined as how long participants retained at least 20% of the improvement in Toronto Western Spasmodic Torticollis Rating Scale or TWSTRS total score seen at week 4.13 Similarly, in the phase 3 ASPEN-1 trial (NCT03608397) phase 3 trial, DAXI 125 U and 250 U had a median duration of effect of 24.0 weeks and 20.3 weeks, respectively.11,14 The BoNT serotype A formulations currently on the market have a median duration of effect of 12 to 14 weeks, requiring more frequent patient visits throughout the year and impacting patient convenience and disease management.11 Short duration of benefit and patient inconvenience are a few of the most common reasons for therapy discontuation.2 With a longer duration of effect, DAXI is a new BoNT formulation that addresses these concerns.

For correspondence:
Kevin Chang, PharmD

1. Tyślerowicz M, Kiedrzyńska W, Adamkiewicz B, Jost WH, Sławek J. Cervical dystonia - improving the effectiveness of botulinum toxin therapy. Neurol Neurochir Pol. 2020;54(3):232-242. doi:10.5603/ PJNNS.a2020.0021
2. Anandan C, Jankovic J. Botulinum toxin in movement disorders: an update. Toxins. 2021;13(1):42. doi:10.3390/toxins13010042
3. Costanzo M, Belvisi D, Berardelli I, et al. Effect of botulinum toxin on non-motor symptoms in cervical dystonia. Toxins (Basel). 2021;13(9):647. doi:10.3390/toxins13090647
4. Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826. doi:10.1212/WNL.0000000000002560
5. Camargo CHF, Teive HAG. Use of botulinum toxin for movement disorders. Drugs Context. 2019;8:212586. doi:10.7573/dic.212586
6. Ramakrishnan NA, Drescher MJ, Drescher DG. The SNARE complex in neuronal and sensory cells. Mol Cell Neurosci. 2012;50(1):58-69. doi:10.1016/j.mcn.2012.03.009
7. Bellows S, Jankovic J. Immunogenicity associated with botulinum toxin treatment. Toxins (Basel). 2019;11(9):491. doi:10.3390/toxins11090491
8. Carr WW, Jain N, Sublett JW. Immunogenicity of botulinum toxin formulations: potential therapeutic implications. Adv Ther. 2021;38(10):5046-5064. doi:10.1007/s12325-021-01882-9
9. Dressler D, Adib Saberi F, Rosales RL. Botulinum toxin therapy of dystonia. J Neural Transm (Vienna). 2021;128(4):531-537. doi:10.1007/s00702-020-02266-z
10. Samadzadeh S, Ürer B, Brauns R, et al. Clinical implications of difference in antigenicity of different botulinum neurotoxin type A preparations: clinical take-home messages from our research pool and literature. Toxins (Basel). 2020;12(8):499. doi:10.3390/toxins12080499
11. Solish N, Carruthers J, Kaufman J, Rubio RG, Gross TM, Gallagher CJ. Overview of daxibotulinumtoxinA for injection: a novel formulation of botulinum toxin Type A. Drugs. 2021;81(18):2091-2101. doi:10.1007/s40265-021-01631-w
12. Revance announces U.S. FDA acceptance of supplemental biologics license application (sBLA) for Daxxify (daxibotulinumtoxinA-lanm) for injection for the treatment of cervical dystonia. News release. Revance Therapeutics Inc. January 6, 2023. Accessed July 6, 2023. revance-announces-us-fda-acceptance-supplemental-biologics
13. Dose-escalating safety and preliminary efficacy of daxibotulinumtoxinA for injection in cervical dystonia. Updated November 6, 2019. Accessed July 6, 2023. https://clinicaltrials. gov/ct2/show/NCT02706795
14. Single treatment of daxibotulinumtoxinA for injection in adults with isolated cervical dystonia (ASPEN-1). Updated December 5, 2022. Accessed July 6, 2023.
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