Ferreira, JJ

Rodrigues, FB

Wild, EJ

English

UCL Discovery

Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=icmo20Current Medical Research and OpinionISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20Physician perception versus true efficacy oftetrabenazine for Huntington’s diseaseFilipe B Rodrigues, Joaquim J Ferreira & Edward J WildTo cite this article: Filipe B Rodrigues, Joaquim J Ferreira & Edward J Wild (2018): Physicianperception versus true efficacy of tetrabenazine for Huntington’s disease, Current MedicalResearch and Opinion, DOI: 10.1080/03007995.2018.1490703To link to this article:  https://doi.org/10.1080/03007995.2018.1490703Accepted author version posted online: 19Jun 2018.Submit your article to this journal View related articles View Crossmark data   COMMENTARY  Physician perception versus true efficacy of tetrabenazine for Huntington’s disease  Filipe B Rodrigues1,2,3, Joaquim J Ferreira2,3,4, Edward J Wild1  1  Huntington’s Disease Centre, University College London, London, UK 2  Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Portugal 3  Instituto de Medicina Molecular, Lisbon, Portugal 4  CNS - Campus Neurológico Sénior, Torres Vedras, Portugal  Correspondence: Filipe B Rodrigues, UCL Huntington’s Disease Centre, Russell Square 10-12, London WC1B 5EH, UK; email: f.rodrigues@ucl.ac.uk    TRANSPARENCY STATEMENT Declaration of funding No funding to disclose.  Declaration of financial/other relationships The authors have no financial or other relationships to disclose. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.  Acknowledgements None reported.       KEYWORDS: Huntington's disease; neurology; movement disorders; tetranenazine   Accepted Manuscript  At the moment there is no cure for Huntington’s disease, so it remains a progressive and ultimately fatal inherited neurodegenerative disorder characterised by motor, cognitive, and behavioural dysfunction, all contributing to cumulative disability and loss of quality of life1-3.   Clinical trials have had a grim success rate, and the evidence to support symptomatic treatment is weak4 5. All this points to a clear need to develop efficacious therapeutic interventions, and to design and conduct successful and informative clinical trials.  Chorea is the most obvious sign of the disease – indeed it was once called Huntington’s chorea. It can be bothersome, contribute to the gait disturbance associated with this condition, and hence the risk of falls, and can cause social stigma; however, it may also go unnoticed, and may not be bothersome6-9.   In a cross-sectional online survey of neurologists practising in the United States of America, Sung and colleagues explored the physician perceptions of benefit of using tetrabenazine for chorea in people with Huntington’s disease. They found that this group of physicians considers treating chorea an important aspect of symptomatic management, but felt limited by the treatment options available at the time of the survey. Tetrabenazine was perceived as a low-to-moderately efficacious intervention with suboptimal tolerability and safety profile, limiting clinical use10.  Some caution is warranted in interpreting these findings. The survey relied on physician recall on the use of tetrabenazine rather than data from objective records or patient reported outcomes. Some questions were asymmetrical, with different numbers of positive and negative response categories. Only US-based practitioners were included. Most of the participants worked in low-volume centres, with only 18% practicing in Huntington’s Disease Society of America Centers of Excellence, and it was unclear how many patients per year each of the participants followed. All these factors limit generalization, especially the fact that the respondants’ experience and knowledge of Huntington’s disease and its therapeutic approaches may have impacted their therapeutic decisions and expectations of benefit. Such issues are all the more important in the presence of potential funding bias: the study was supported by a corporation that developed and owns the only other FDA-approved competing therapeutic agent for chorea in Huntington’s disease - deutetrabenazine.  As of today, tetrabenazine and deutetrabenazine are the only FDA-approved interventions for chorea in Huntington’s disease, while in Europe, only the former is available. Tetrabenazine is widely used across Europe, as it is in North America and in Australia, and off-label anti-psychotic drugs are also regularly prescribed by physicians across the globe, which may be more effective or better tolerated than existing treatments that are specifically licensed for HD; much more work is needed to compare all these drugs head to head.11-13  Tetrabenazine and deutetrabenazine are also the only two drugs with positive randomized controlled trials. In the TETRA study, tetrabenazine had a mean effect of -3.5 units in the UHDRS total maximal chorea score (range: 0, absent chorea, to 28, marked/prolonged chorea in 7 different body segments); while in the FIRST-HD study, deutetrabenazine had a mean effect of -2.5 units in the same score, both against a placebo intervention14 15.  Sung and colleagues evaluated physician perception of benefit in real-world clinical practice. An analogous measurement of global effect may be inferred from the results generated in clinical trials: in the absence of a placebo group, we can assess the mean change from baseline in the active arms of these trials (-5 and -4.4 units in the UHDRS total maximal chorea score for TETRA and FIRST-HD, respectively). Even after accounting for the placebo effect, these results were considered by the participants and the clinicians in these trials to be relevant, and led to the approval of these drugs14 15.   In line with prior evidence, Sung and colleagues confirmed that the most frequent reasons why clinicians decide to treat chorea have to do with social and family embarrassment, impact of functional ability and quality of life, and risk of injuries10 11. Still, there is uncertainty as to whether the available interventions have a beneficial impact on these underlying factors, as opposed to the visible movement disorder per Accpted Manuscript  se16 17. The picture drawn by the survey about the safety profile of tetrabenazine is very much in line with data from the TETRA study14.  An important question remains to be answered: will real-world use of deutetrabenazine produce a different perception of benefit? Little is known about how tetrabenazine and deutetrabenazine compare to each other. No head-to-head evaluation has been performed or is planned, and indirect treatment comparisons have controversial results18-20. Based on the FIRST-HD study results, we anticipate that deutetrabenazine will likely produce similar perception to what was detected in this survey.  Nonetheless, we affirm Sung and colleagues’ core finding that the symptomatic interventions available for people with Huntington’s disease are limited, leaving significant unmet need. Even though targeted interventions to modify the underlying pathology appear to be closer than ever21 22, there will always be a need for efficacious, safe, tolerable and evidence-based symptomatic treatments.   Accepted Manuscript  References 1.  Mestre T, Ferreira J, Coelho MM, et al. Therapeutic interventions for disease progression in Huntington's disease. Cochrane Database Syst Rev 2009(3):CD006455. doi: 10.1002/14651858.CD006455.pub2 2.  Rodrigues FB, Abreu D, Damasio J, et al. Survival, mortality, causes and places of death in a European Huntington's disease prospective cohort. Mov Disord Clin Prac 2017;4(5):737-42. doi: 10.1002/mdc3.12502 3.  Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers 2015;1:15005. doi: 10.1038/nrdp.2015.5 4.  Mestre T, Ferreira J, Coelho MM, et al. Therapeutic interventions for symptomatic treatment in Huntington's disease. Cochrane Database Syst Rev 2009(3):CD006456. doi: 10.1002/14651858.CD006456.pub2 5.  Travessa AM, Rodrigues FB, Mestre TA, et al. Fifteen years of clinical trials in Huntington's disease: a very low clinical drug development success rate. J Huntingtons Dis 2017;6(2):157-63. doi: 10.3233/JHD-170245 6.  Snowden JS, Craufurd D, Griffiths HL, et al. Awareness of involuntary movements in Huntington disease. Arch Neurol 1998;55(6):801-5. [published Online First: 1998/06/17] 7.  Ross CA, Pantelyat A, Kogan J, et al. Determinants of Functional Disability in Huntington’s Disease: Role of Cognitive and Motor Dysfunction. Movement disorders : official journal of the Movement Disorder Society 2014;29(11):1351-58. doi: 10.1002/mds.26012 8.  Shoulson I. Huntington Disease - Functional Capacities in Patients Treated with Neuroleptic and Anti-Depressant Drugs. Neurology 1981;31(10):1333-35. doi: Doi 10.1212/Wnl.31.10.1333 9.  McCusker E, Loy CT. The many facets of unawareness in huntington disease. Tremor Other Hyperkinet Mov (N Y) 2014;4:257. doi: 10.7916/d8fj2fd3 [published Online First: 2014/11/21] 10.  Sung VW, Iyer RG, Gandhi SK, et al. Physician perceptions of pharmacologic treatment options for chorea associated with Huntington disease in the United States. Curr Med Res Opin 2018:1-6. doi: 10.1080/03007995.2018.1435518 11.  Burgunder JM, Guttman M, Perlman S, et al. An international survey-based algorithm for the pharmacologic treatment of chorea in Huntington's disease. PLoS Curr 2011;3:RRN1260. doi: 10.1371/currents.RRN1260 12.  Orth M, Handley OJ, Schwenke C, et al. Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY. PLoS Curr 2010;2:Rrn1184. doi: 10.1371/currents.RRN1184 [published Online First: 2010/10/05] 13.  Brusa L, Orlacchio A, Moschella V, et al. Treatment of the symptoms of Huntington's disease: preliminary results comparing aripiprazole and tetrabenazine. Movement disorders : official journal of the Movement Disorder Society 2009;24(1):126-9. 14.  Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006;66(3):366-72. doi: 10.1212/01.wnl.0000198586.85250.13 [published Online First: 2006/02/16] 15.  Huntington Study Group. Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial. Jama 2016;316(1):40-50. 16.  Fekete R, Davidson A, Jankovic J. Clinical assessment of the effect of tetrabenazine on functional scales in huntington disease: a pilot open label study. Tremor Other Hyperkinet Mov 2012;2(5):1-8. doi: 10.7916/D8DN43SC 17. Ferrara JM, Mostile G, Hunter C, et al. Effect of tetrabenazine on motor function in patients with huntington disease. Neurology and therapy 2012;1(1):5. doi: 10.1007/s40120-012-0005-7 [published Online First: 2012/12/01] 18. Rodrigues FB, Duarte GS, Costa J, et al. Tetrabenazine versus deutetrabenazine for Huntington's disease: twins or distant cousins? Eur J Neurol 2017;4(4):582-85. doi: 10.1002/mdc3.12483 19.  Claassen DO, Carroll B, De Boer LM, et al. Indirect tolerability comparison of deutetrabenazine and tetrabenazine for Huntington disease. J Clin Mov Disord 2017;4:3. doi: 10.1186/s40734-017-0051-5 20.  Rodrigues FB, Duarte GS, Costa J, et al. Meta-research metrics matter: letter regarding article "indirect tolerability comparison of deutetrabenazine and tetrabenazine for Huntington disease". J Clin Mov Disord 2017;4:19. Accpted Manuscript  21.  Rodrigues FB, Wild EJ. Huntington’s disease clinical trials corner: February 2018. Journal of Huntington's Disease 2018;7(1):87-97. 22.  Rodrigues FB, Wild EJ. Clinical Trials Corner: September 2017. Journal of Huntington's disease 2017;6(3):255-63.  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Physician perception versus true efficacy of tetrabenazine for Huntington's disease

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Physician perception versus true efficacy of tetrabenazine for Huntington's disease

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