Pharmaceuticals / Submissions and Approvals
Teva Wins Breakthrough Therapy Designation for Tardive Dyskinesia Candidate
Teva Pharmaceutical Industries has won the FDA’s breakthrough therapy designation for SD-809 for the treatment of moderate to severe tardive dyskinesia.
An oral, small molecule inhibitor of vesicular monoamine 2 transporter, SD-809 (deutetrabenazine) is designed to regulate the levels of dopamine in the brain. There are currently no approved therapies in the U.S. for tardive dyskinesia, a disorder characterized by repetitive and uncontrollable movements of the tongue, lips, face and extremities.
The Israeli drugmaker’s 117-patient Phase 2/3 study compared SD-809 to placebo for reducing the severity of abnormal involuntary movements associated with tardive dyskinesia. The compound also is being developed for treatment of chorea associated with Huntington’s disease, as well as tics associated with Tourette syndrome.
Tardive dyskinesia: a brief explanation
Tardive dyskinesia is a disorder that involves involuntary movements. Most commonly, the movements affect the lower face. Tardive means delayed and dyskinesia means abnormal movement.
Causes
Tardive dyskinesia is a serious side effect that occurs when you take medications called neuroleptics. Most often, it occurs when you take the medication for many months or years. In some cases, it occurs after you take them for as little as 6 weeks.
The drugs that most commonly cause this disorder are older antipsychotic drugs, including:
- Chlorpromazine
- Fluphenazine
- Haloperidol
- Trifluoperazine
Other drugs, similar to these antipsychotic drugs, that can cause tardive dyskinesia include:
- Flunarizine
- Metoclopramide
- Prochlorperazine
Newer antipsychotic drugs seem less likely to cause tardive dyskinesia, but they are not entirely without risk.
Symptoms
Symptoms of tardive dyskinesia may include:
- Facial grimacing
- Finger movement
- Jaw swinging
- Repetitive chewing
- Tongue thrusting
Treatment
When the drug is stopped early enough, the movements may stop.
Medications to reduce the severity of the movements may also help. Botulinum toxin (Botox) injections may be effective.
Outlook (Prognosis)
If diagnosed early, the condition may be reversed by stopping the drug that caused the symptoms. Even if the drug is stopped, the involuntary movements may become permanent, and in some cases, may become worse.
References
Flaherty AW. Movement disorders. In: Stern TA, Rosenbaum JF, Fava M, et al., eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry. 1st ed. Philadelphia, PA: Elsevier Mosby; 2008:chap 80.
Kompoliti K, Horn SS, eds. Drug-induced and iatrogenic neurological disorders. In: Goetz CG, ed. Textbook of Clinical Neurology. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2007:chap 55.
Please watch these two VIDEOS on Extrapyramidal Syndromes and Movement disorders
Monoamine transporters and movement disorder
Links between the monoamine transporter VMAT2 (SLC18A2 gene) and tardive dyskinesia
Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia.
Abstract
Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.
Other journal articles related to VMAT2
- VMAT2 genetic variants contribute to the phenotypes of alcohol dependence.
- Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles.
- In an Italian cohort, variability in VMAT2 promoter region appears to confer a reduced risk of developing Parkinson’s disease.
- VMAT2 expression dynamically decreased in the neocortex of temporal lobe epilepsy patients when compared with the control subjects.
- Data suggest that pancreatic islets of humans and pigs contain VMAT2 in similar patterns (in beta cells, mast cells, and sympathetic neurons); therefore, the pig (unlike rodents) is potential model for imaging pancreas using radioligands for VMAT2.
- Chromogranin A and vesicular monoamine transporter 2 are localized in protein bodies of human locus coeruleus neurons.
- These results may indicate that VMAT2 expressed in noradrenergic neurons has crucial roles in survival during the first several weeks after birth, and VMAT2 functions in other monoaminergic systems could be required for further extended survival.
- Study evaluated VMAT2 specificity for beta cells in sub-regions of the human pancreas using antibodies targeting VMAT2, insulin and PP by double-label immunofluorescence.
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