Breakthrough drugs for the interface between psychiatry and neurology (2016)

The US Food and Drug Administration (FDA) has made several different options available for the expedited review or ‘special handling’ of drugs and biologics 1-3. One option is called Breakthrough Therapy status 1-3. Breakthrough Therapy status is available for ‘a drug that is intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies’ 1. The designation enables the FDA to provide ‘intensive guidance on efficient drug development, organizational commitment, rolling review and other actions to expedite review’ 1. The end result is that effective treatments can be made available sooner, which is of critical importance when the available therapeutic options are limited or non-existent. Unmet needs are present in ‘neuropsychiatry.’ The interface between psychiatry and neurology includes disorders where psychiatric phenomenology is associated with a neurological condition, such as Parkinson's disease psychosis 4, and disorders where abnormal movements are associated with the use of antipsychotic medications, as for example tardive dyskinesia 5, 6. Presently, there are no FDA-approved medications specifically indicated for either Parkinson's disease psychosis or tardive dyskinesia. This may soon change. The FDA has granted Breakthrough Therapy status for pimavanserin for Parkinson's disease psychosis 7, valbenazine for tardive dyskinesia 8 and deutetrabenazine for tardive dyskinesia 9. Up until now, the treatment options for both of these neuropsychiatric conditions have been very limited. It is unfortunate that psychotic symptoms are common in patients with Parkinson's disease; these include visual hallucinations and paranoid delusions, and generally carry a poor prognosis 4. Although ‘off-label,’ clozapine has demonstrated excellent efficacy in treating these symptoms 10. Enthusiasm for clozapine is dampened by concerns regarding hematological, metabolic, gastrointestinal, and cardiac adverse effects 11. Alternatives are urgently needed. Pimavanserin is a selective serotonin 5-HT2A inverse agonist without dopaminergic, adrenergic, histaminergic or muscarinic affinity 12. In a Phase III, 6-week, randomised, double-blind, placebo-controlled study, patients with Parkinson's disease psychosis demonstrated clinically relevant improvement on their psychotic symptomatology with pimavanserin 40 mg 12. The response rate, defined by a Clinical Global Impressions–Improvement score of very much improved or much improved, showed an advantage for pimavanserin vs. placebo of 49% vs. 23%, for a number needed to treat (NNT) of 4. Crucially, there were no significant safety concerns or worsening of motor function. Tardive dyskinesia has long been thought to be a generally irreversible consequence of antipsychotic medication use. Characterised by involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, upper extremities, lower extremities and respiratory system, this disorder can be quite stigmatising 5. Up to now, suggested treatments have been ineffective or limited 6. Tetrabenazine, an agent approved in the USA in 2008 as an orphan drug for the treatment of choreiform movements associated with Huntington's Disease, and available elsewhere before then, has been used to treat tardive dyskinesia ‘off-label’ 13. Tetrabenazine is an inhibitor of the vesicular monoamine transporter 2 (VMAT-2), resulting in synaptic dopamine depletion. However, its pharmacokinetic profile requires frequent dosing and side effects include drowsiness, parkinsonism, and depression 13. Two other VMAT-2 inhibitors are being developed that promise to be easier to use, valbenazine and deutetrabenazine. Deutetrabenazine is a variant of tetrabenazine; the incorporation of deuterium in place of hydrogen at the sites of primary metabolism results in metabolic clearance being slowed, allowing less frequent dosing and better tolerability 14. A successful Phase II/III, randomised, double-blind, placebo-controlled, parallel-group study in patients with moderate to severe tardive dyskinesia was announced 15, and other trials are in progress (NCT02291861, NCT02198794). Valbenazine is a new molecular entity which is metabolised to its active derivative (+)-α-dihydrotetrabenazine; the potentially undesirable dihydrotetrabenazine derivatives of β-tetrabenazine are not produced 8. The pharmacokinetic profile permits once daily dosing. In a randomised, 6-week, double-blind, placebo-controlled, dose-titration study, valbenazine significantly improved tardive dyskinesia and was well tolerated 16. Responder rates (defined as a ≥ 50% improvement in the tardive dyskinesia rating scale used in the study) were 48.9% for valbenazine vs. 18.2% for placebo, for a NNT of 4. Clinical Global Impression of Change of very much improved or much improved was observed in 66.7% vs. 15.9% of participants randomised to valbenazine and placebo, respectively, for a NNT of 2. Positive findings from a Phase III study have also been announced 17 and an additional study is in progress (NCT02405091). It is heartening to see drug development progressing and providing greater opportunities for the successful management of difficult medical conditions. Kudos to the FDA for actively helping this process along. No external funding or writing assistance was utilised in the production of this editorial. In the past 36 months Leslie Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Acadia, Alexza, Alkermes, Allergan, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Neurocrine, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant.