Dementia is associated with agitation, induced at least in part by pain, making patients dangerous to themselves and others. Risperidone and off-label psychotropic drugs act by a non-specific mechanism, double the risk of death and increase treatment and hospitalization costs. Bergamot essential oil (BEO) provided high quality preclinical evidence of analgesic activity. BEO was defurocoumarinized to avoid phototoxicity and encapsulated in the NanoBEO nanotechnological device [TRL6; patent granted in Italy (IT201900013353A1) and in the European Regional phase (EP4003294A1)] for clinical translation. NanoBEO is the first treatment of agitation for patients affected by severe dementia needs-oriented, safe, effective and administrable for a long time.
Patent Status
SUBMITTED
Priority Number
102019000013353
Priority Date
30/07/2019
License
INTERNATIONAL
Market
Through international literature (World Alzheimer Report) a Total Addressable Market (TAM) of over 55 million patients was traced with a trend to triple by 2050. The Served Addressable Market (SAM) was identified through market research that was direct (surveys with pharmacologists, neurologists and neuropsychiatrists of the German Center for Neurodegenerative Diseases, DZNE) and indirect (Alzheimer Europe 2019 Yearbook) in a total of 7,853,705 patients, representing the segment of the population suffering from dementia in Europe. The segmentation based on direct market surveys conducted with neurologists, operators and general practitioners of the referral health district and with national patient associations, provides the following Serviceable Obtainable Market (SOM): 0.25% of the SAM equal to 19,634 patients in the first year after the NanoBEO launch on the market; 0.75% of the SAM equal to 58,903 patients in the second year and 1.4% of the SAM equal to 109,952 patients in the third year.
Problem
According to the World Alzheimer report, 55 million people worldwide suffer from dementia and this number is estimated to triple by 2050. Dementia is mainly found in the population of people over 65, very often presenting comorbidities accompanied by chronic, inflammatory and neuropathic pain, often under-diagnosed. Approximately 60%–80% of dementia patients admitted to nursing homes experience pain. Neuropsychiatric symptoms of dementia such as agitation are closely associated with underdiagnosed and undertreated pain (Sengstaken et al., 1993, J. Am. Geriatr. Soc., 41, 541–544.; Sampson et al., 2015, Pain, 156, 675–683.) and, therefore, undetected and not appropriately treated (Scherder et al., 2009, Pain, 145, 276–278.; Husebo et al., 2011, Int. J. Geriatr. Psychiatry, 26 , 1012–1018.). The 97% of dementia patients develops agitation which reduces quality of life.
Current Technology Limits
The study of the effects of antipsychotics in the treatment of primary neuropsychiatric disorders led to their off-label use in dementia, regardless of the differences between primary and secondary disorders in terms of neuropsychopathology and, consequently, of drug efficacy and safety. The categories of drugs currently used (even off-label) and most studied in clinical trials for the management of agitation in dementia are as follows: drugs for the therapy of cognitive decline (acetylcholinesterase inhibitors and memantine), classic and atypical antipsychotics (e.g. haloperidol, olanzapine, perphenazine, risperidone); antidepressants (eg, tricyclic antidepressants, trazodone and venlafaxine and selective serotonin reuptake inhibitors, such as sertraline and, more recently, citalopram and escitalopram); anticonvulsants and mood stabilizers (e.g. carbamazepine, gabapentin, valproic acid); finally, benzodiazepines such as lorazepam. Furthermore, due to the involvement of multiple neurotransmitter systems in dementia-related agitation, an investigational new drug, lumateperone tosylate, is under investigation because it possesses several potentially useful pharmacological mechanisms. Only the antipsychotic risperidone is approved for treatment, but no longer than 6 weeks due to doubled risk of death (Schneider et al., 2005, JAMA: 294(15):1934-43). Aromatherapy with an essential oil with powerful analgesic activity is a very useful approach for the control of agitation (Scuteri et al., 2017, Evid Based Complement. Altern. Med. eCAM, 2017, 9416305). However, aromatherapy has not provided robust evidence of efficacy due to methodological biases (Ballard et al., 2009, Nat Rev Neurol 5(5):245-55).
Killer Application
Bergamot essential oil (BEO; Citrus bergamia Risso et Poiteau) is the sole essential oil to have proven efficacy in pain models relevant to the clinical condition of interest (Scuteri et al., Front Pharmacol.;12:640128). A delivery system for BEO was developed on a nanotechnological basis and in the pharmaceutical form of a cream, NanoBEO, which confirms the analgesic properties of BEO and makes its rational clinical use possible (Scuteri et al., Pharmaceutics;13(3 ):379) because it allows: 1) to encapsulate the phytocomplex devoid of furocoumarins and to titrate the active principles; 2) the stability of the activity for very long time compared to the essential oil as it is (sensitive to physical, chemical agents, etc.); 3) reproducible effects and long-term treatment; 4) the overcoming of the issue posed by the diffusion of the aroma and, therefore, of its recognition by the patient and the healthcare operator, preventing the conduct of double-blind clinical trials. NanoBEO guarantees efficacy and safety and it has been patented (IT201900013353A1) and it is now in the European Regional phase (EP4003294A1).
Our Technology and Solution
The analgesic characteristics of bergamot essential oil (BEO) have been documented in over a decade preclinical researches (Morrone et al., 2007, Pharmacol Res.;55(4):255-62; Sakurada et al., 2009; Int Rev Neurobiol.;85:237-48; Sakurada et al., 2011; Pharmacol Biochem Behav.;97(3):436-43; Kuwahata et al., 2013; Pharmacol Biochem Behav.;103(4):735- 41; Katsuyama et al., 2015; Biomed Res.;36(1):47-54; Scuteri et al., 2022 Curr Pharm Des.; 28(20):1607-1610). This TRL1 phase together with the documented need for a special formulation for translation of this natural product into the clinical setting of neuropsychiatric disorders, induced at least in part by pain in dementia, form the basis for the conceptualization and proof of concept of BEO encapsulated in a nanotechnological device (TRL2-3 phase) (Scuteri et al., 2021, Pharmaceutics;13(3):379). The latter system was experimentally validated to demonstrate in laboratory that it is endowed with the fundamental technological characteristics for the expression of the typical activity of the natural product in the preclinical setting of inflammatory and neuropathic pain, using the same experimental models used for BEO as phytocomplex (TLR4). Based on this validation, a reliable airless dispenser of known quantities of cream was identified, i.e. the nanotechnological device containing the defurcoumarinized natural product (BEO) NanoBEO (TRL6) for use in the relevant clinical setting (moderate to severe dementia) (TLR7-9) (Scuteri et al., 2021; Phytother Res.;35(10):5333-5338; Scuteri et al., 2022; Molecules;27(15):4987).
Advantages
NanoBEO allows to administer a defined, and stable over time, dose of the phytocomplex titrated in the main components, protected from chemical-physical instability. This guarantees a high shelf-life and provides the first needs-oriented treatment of agitation for patients suffering from severe dementia, that is safe, effective and administrable for a long time. NanoBEO is free of side effects and allows to treat dementia-related agitation with a device oriented to patients’ unmet needs, specifically formulated for this condition and which guarantees the constant and reproducible effects of a defined, titrated dose and stable for the first time. In fact, the main competitors of NanoBEO act on agitation with a non-specific mechanism, double the risk of death and increase the costs for patient care and hospitalization due to the onset of strokes and myocardial infarctions and the worsening of cognitive impairment with accidents and falls (Scuteri et al., 2019. Curr Med Chem;26(20):3764-3774; Scuteri et al., 2019. Int J Mol Sci.;20(13):3327).
TRL
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