(19)
(11)EP 3 265 087 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
22.07.2020 Bulletin 2020/30

(21)Application number: 16711931.2

(22)Date of filing:  04.03.2016
(51)International Patent Classification (IPC): 
A61K 31/4439(2006.01)
A61P 17/04(2006.01)
(86)International application number:
PCT/US2016/021015
(87)International publication number:
WO 2016/141341 (09.09.2016 Gazette  2016/36)

(54)

METHOD OF TREATMENT WITH TRADIPITANT

VERFAHREN ZUR BEHANDLUNG MIT TRADIPITANT

PROCÉDÉ DE TRAITEMENT AVEC TRADIPITANT


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 04.03.2015 US 201562128472 P
25.09.2015 US 201562232644 P

(43)Date of publication of application:
10.01.2018 Bulletin 2018/02

(60)Divisional application:
20180523.1

(73)Proprietor: Vanda Pharmaceuticals Inc.
Washington, DC 20037 (US)

(72)Inventors:
  • POLYMEROPOULOS, Mihael, H.
    Potomac, MD 20854 (US)
  • LICAMELE, Louis, William
    Potomac, MD 20854 (US)

(74)Representative: Appleyard Lees IP LLP 
15 Clare Road
Halifax HX1 2HY
Halifax HX1 2HY (GB)


(56)References cited: : 
WO-A1-2019/055225
US-A1- 2014 378 521
  
  • GEORGE D T; GILMAN J: "Neurokinin 1 receptor Antagonism as a possible therapy for alcoholism", SCIENCE, vol. 319, no. 5869, 14 March 2008 (2008-03-14), pages 1536-1539, XP055273714, US ISSN: 0036-8075, DOI: 10.1126/science.1153498
  • D. T. GEORGE ET AL: "Supporting Online Material for Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism", SCIENCE, vol. 319, no. 5869, 14 March 2008 (2008-03-14), pages 1536-1539, XP055273730, US ISSN: 0036-8075, DOI: 10.1126/science.1153813
  • SONJA STÄNDER ET AL: "Targeting the Neurokinin Receptor 1 with Aprepitant: A Novel Antipruritic Strategy", PLOS ONE, vol. 5, no. 6, 1 January 2010 (2010-01-01) , pages e10968-e10968, XP055089771, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0010968
  • TAUSCHER J ET AL: "Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder", EUROPEAN NEUROPSYCHOPHARMACOLOGY, ELSEVIER SCIENCE PUBLISHERS BV, AMSTERDAM, NL, vol. 20, no. 2, 1 February 2010 (2010-02-01), pages 80-87, XP026827192, ISSN: 0924-977X [retrieved on 2009-12-16]
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

CROSS REFERENCE TO RELATED APPLICATIONS



[0001] This application claims the benefit of co-pending US Provisional Applications No. 62/128,472, filed 04 March 2015, and No. 62/232,644, filed 25 September 2015.

BACKGROUND



[0002] Chronic pruritus affects millions of people worldwide and represents a serious and unmet medical need. The itch sensation is believed to be induced at least in part through the action of the endogenous neuropeptide substance P (SP), through the binding at NK-1Rs expressed on multiple skin cells.

[0003] The NK-1R is expressed throughout different tissues of the body, with major activity found in neuronal tissue. SP and NK-1R interactions in neuronal tissue regulate neurogenic inflammation locally and the pain perception pathway through the central nervous system. Other tissues, including endothelial cells and immune cells, have also exhibited SP and NK-1R activity. The activation of NK-1R by the natural ligand SP is involved in numerous physiological processes, including the perception of pain, behavioral stressors, cravings, and the processes of nausea and vomiting. An inappropriate over-expression of SP either in nervous tissue or peripherally could result in pathological conditions such as substance dependence, anxiety, nausea/vomiting, and pruritus. An NK-1R antagonist may possess the ability to reduce this over-stimulation of the NK-1R, and as a result address the underlying pathophysiology of the symptoms in these conditions.

[0004] Tradipitant is a neurokinin-1 receptor antagonist formerly known as VLY-686, having the chemical names 2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone and {2-[1-(3,5-Bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, and the following chemical structure:

Tradipitant is disclosed in US Pat. 7,320,994, and contains six main structural components: the 3,5-bis-trifluoromethylphenyl moiety, two pyridine rings, the triazol ring, the chlorophenyl ring and the methanone. Crystalline Forms IV and V of tradipitant are disclosed in US Pat. 7,381,826. A process for synthesizing tradipitant is disclosed in US Pat. 8,772,496.

[0005] US Publication No. 2014/0378521 discloses a pharmaceutical composition comprising the NK-1 receptor agonist serlopitant. Also disclosed is a method for treating acute or chronic pruritus with various dosages of the NK-1 receptor agonist serlopitant.

[0006] Sonja Ständer, et al., Targeting the Neurokinin Receptor 1 with Aprepitant: A Novel Antipruritic Strategy, PLOS ONE, vol. 5, no. 6, pp. e10968-e10968 (1st January 2010) discloses targeting of the neurokinin receptor 1 with aprepitant as a potential antipruritic strategy. A high response rate in patients with therapy refractory pruritus suggested that aprepitant may exhibit antipruritic effects and may present a novel, effective treatment strategy.

BRIEF DESCRIPTION OF THE INVENTION



[0007] The invention is defined in the appended claims.

[0008] Disclosed is the administration of tradipitant to a patient in need thereof which comprises internally administering to the patient tradipitant in an amount and at a frequency of administration sufficient to achieve and to maintain a plasma concentration of > 100 ng/mL.

[0009] Also disclosed is the administration of tradipitant to a patient in need thereof which comprises internally administering an effective amount of tradipitant to the patient. The effective amount may be, e.g., 100 to 400 mg/day, 100 to 300 mg/day, or 100 to 200 mg/day. The effective amount may be administered twice daily, i.e., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85 mg bid.

[0010] Further disclosed is use of tradipitant for the treatment of pruritus by internally administering to a patient suffering from pruritus by internally administering to the patient tradipitant in an amount and at a frequency of administration sufficient to achieve and to maintain a plasma concentration of > 100 ng/mL, i.e., an effective amount of tradipitant.

[0011] Also disclosed is the use of tradipitant for the preparation of a medicament for the treatment of pruritus by internally administering to the patient tradipitant in an amount and at a frequency of administration sufficient to achieve and to maintain a plasma concentration of > 100 ng/mL, i.e., an effective amount, e.g., an amount of 85 mg bid, 85 mg qd, 100 mg qd, or other dosing regimen.

[0012] A dose can be 85 to 170 mg/day. This may be, e.g., 85 mg bid, 85 mg qd, 100 mg qd, or 100 mg bid.

BRIEF DESCRIPTION OF THE DRAWINGS



[0013] 

FIG. 1 provides a scatter plot of serum levels of tradipitant, showing concentration weight vs. visit time.

FIG. 2 provides a scatter plot of VAS change vs. concentration-weight of tradipitant (Spearman correlation P-value = 0.0204).


DETAILED DESCRIPTION OF THE DISCLOSURE



[0014] At least one embodiment of the present disclosure is described below in reference to its application in connection with the use of tradipitant for the treatment of chronic pruritus. Although embodiments of the disclosure are illustrated relative to specific dosing regimens, e.g., 100 mg qd, 85 mg bid, and 85 mg qd, it is understood that the teachings are equally applicable to other dosing regimens, e.g., 100 to 400 mg/day, 100 to 300 mg/day, 100 to 200 mg/day, or about 85-170 mg/day, which may be administered as, e.g., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85 mg bid.

[0015] As used herein, the term "patient" refers to a mammal that is afflicted with one or more disorders ameliorated by administration of tradipitant, e.g., pruritus. Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of mammals within the scope of the meaning of the term. It will be understood that the most preferred patient is a human.

[0016] It is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of tradipitant. Thus, the terms "treatment" and "treating" are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, and is intended to include prophylactic treatment of such disorders, but does not necessarily indicate a total elimination of all disorder symptoms.

[0017] As used herein, the term "effective amount" of tradipitant refers to an amount that is effective in treating the disorders described herein.

[0018] With regard to dosing, "qd" refers to dosing once per day; bid dosing typically means dosing once in the morning and once in the evening, generally no less than about 8 hours or more than about 16 hours apart, e.g., 10 to 14 hours or 12 hours (Q12H).

[0019] The skilled artisan will appreciate that additional preferred embodiments may be selected by combining the preferred embodiments above, or by reference to the examples given herein.

EXAMPLE 1



[0020] A phase II proof of concept clinical study (Study ID VP-VLY-686-2101, "Proof of Concept of VLY-686 in Subjects With Treatment-Resistant Pruritus Associated With Atopic Dermatitis") was conducted, investigating the safety and efficacy of tradipitant as a monotherapy in the treatment of chronic pruritus in patients with atopic dermatitis.

[0021] Despite a highly significant and clinically meaningful improvement from baseline by tradipitant (40.5mm improvement from baseline, p<0.0001) as measured on a 100mm unit Visual Analog Scale (VAS) for itch, a very high placebo effect (36.5 mm improvement from baseline, p<0.0001) on the change from baseline led to no statistical difference from placebo. However, subsequent analysis of population PK samples across all patients in the study revealed significant and clinically meaningful responses across multiple outcomes evaluated in individuals with higher levels of tradipitant exposure at the time of their pruritus assessments.

[0022] The pre-specified primary endpoint of the Phase II proof of concept clinical study was the change from baseline on the Visual Analog Scale (VAS) for itch. Due to high placebo effect, there was no significant difference from placebo on this pre-specified endpoint. However, in subsequent analyses it has been discovered that there is an exposure response relationship. It has further been observed that there is a significant and clinically meaningful response across several pruritus related outcomes evaluated in individuals with higher blood plasma levels of tradipitant. Based on the data examined across the study, lower blood plasma levels of tradipitant may be below a threshold of efficacy to ameliorate the itch sensation in patients.

METHODS



[0023] In the study, patients with a Visual Analog Scale (VAS) score of greater than 70mm during one of the two days preceding inclusion into the study were randomized to receive orally either 100 mg of tradipitant (N=34) or placebo (N=35) once a day in the evening. In the tradipitant arm of the study, tradipitant was orally administered to patients in capsules with standard excipients in an amount of 100 mg in the evening. Clinical assessments were made after 3 or 4 weeks of daily treatment, or at both 3 weeks and 4 weeks, each assessment being done in the morning of the day after last treatment or in the afternoon of the day after last treatment. The tradipitant was administered in an immediate release form comprising tradipitant and pharmaceutically acceptable excipients in a capsule. The tradipitant particle size was approximately: D10: < 5 um, D50: < 10 um, and D90: <25 um, wherein D10 means that 10% of the particles are of the indicated mean particle size, D50 means that 50% of the particles are of the indicated mean particle size, and D90 means that 90% of the particles are of the indicated mean particle size.

[0024] Baseline VAS scores were 76.1 and 77.2 for the tradipitant and placebo arms respectively. Efficacy was evaluated through a number of clinical research instruments. In addition, at the time of efficacy evaluation blood samples were collected for PK analysis in order to determine the plasma levels of tradipitant.

RESULTS



[0025] A PK-PD (pharmacokinetic-pharmacodynamics) analysis in the tradipitant treatment arm showed a significant correlation between blood levels of tradipitant and the VAS change from baseline (p<0.05). Individuals with higher circulating levels of tradipitant at the time of the efficacy evaluation demonstrated higher magnitude of response. A separate PK analysis of the time of pruritus assessment revealed that approximately half the patients in the study came in for morning (AM group, ∼12 hours post-dose) visits for their pruritus assessments and that these patients also had higher blood levels of tradipitant than those who came in the afternoon (PM group, ∼18 hours post-dose).

[0026] The average plasma concentrations of tradipitant across AM and PM-evaluated patients were between about 125 ng/mL and about 225 ng/mL. Patients evaluated in the afternoons (PM) (mean = about 20 hours post last administration) tended to have lower plasma concentrations of tradipitant than patients evaluated in the mornings (AM) (mean = about 15 hours post last administration). The average plasma concentration in the PM group was about 125 ng/mL, and the average plasma concentration in the AM group was about 225 ng/mL, the difference being largely attributable to the length of time post administration. More significantly, the results show a correlation between plasma concentration and efficacy, whereby patients in whom the plasma concentrations were >100 ng/mL (e.g., about 125 ng/mL or greater, about 150 ng/mL or greater, about 175 ng/mL or greater, about 200 ng/mL or greater, or about 225 ng/mL or greater) tended to show greater efficacy than patients with lower plasma concentrations.

[0027] A further analysis of the AM group revealed significant and clinically meaningful effects of tradipitant as compared to placebo and is shown in Table 1. Higher concentrations of tradipitant were associated with higher efficacy in treating chronic pruritus in the study. A similar analysis in the PM group showed no significant differences between tradipitant and placebo.
Table 1: Group efficacy analysis of pruritus measures
 AM PM
 Tradi pitantPlaceboDiffP-value Tradi pitantPlaceboDiffP-value
 N=18N=17   N=13N=11  
Primary         
VAS Average change -54 -30.3 -23.7 0.007   -28.8 -34.6 5.82 0.6701
Secondary         
VAS Worst change -47.9 -26 -21.9 0.0302   -32.3 -41.3 8.99 0.5153
VRS change -1.46 -0.67 -0.79 0.0496   -1.29 -1.16 -0.13 0.7881
DLQI change -2.52 -2.87 0.35 0.8458   -5.45 -3.56 -1.89 0.2423
PBI 1.47 0.73 0.74 0.0393   1.01 1.4 -0.39 0.4696
CGIC 2.46 3.61 -1.15 0.0497   2.47 2.29 0.19 0.7452
SCORAD change -9.58 -4.36 -5.23 0.0027   -6.29 -7.18 0.88 0.7061
Table 1 abbreviations: Visual Analog Scale (VAS), Verbal Rating Scale (VRS), Dermatology Life Quality Index (DLQI), Clinical Global Impression of Change (CGI-C), Patient Benefit Index (PSI), SCORing Atopic Dermatitis Index (SCORAD).


[0028] This data is consistent with the hypothesis that tradipitant, an NK-1R antagonist, may offer symptomatic relief in patients with pruritus (VAS, VRS, SCORAD subjective). Endpoints were also collected in the study that correspond to the underlying disease (SKINDEX, SCORAD objective, EASI and DLQI). These results did not show any significant difference from placebo which would be expected from a drug targeting the symptom of itch in a short-term 4-week study. Importantly, as pruritus, the intractable itching associated with atopic dermatitis, is the major complaint of patients, the effects that were also seen in the CGI-C scale and the PBI scales suggest a recognizable overall clinically meaningful effect from both the clinician and the patient perspective.

CONCLUSIONS



[0029] These data support the premise that in patients suffering pruritus, e.g., pruritus associated with atopic dermatitis, patients can be treated by orally administering tradipitant, e.g., Form IV or Form V (or a pharmaceutically acceptable salt thereof) in amounts and at a dosing frequency required to achieve plasma concentrations of at least about 100 ng/mL, e.g., 125 ng/mL or greater, 150 ng/mL or greater, 175 ng/mL or greater, 200 ng/mL or greater, or 225 ng/mL or greater. Such plasma concentration levels can be achieved, e.g., by orally administering the tradipitant in immediate release solid dosage forms once per day at a higher dose or in immediate release forms with improved bioavailability or in controlled release forms, or by orally administering the tradipitant multiple times per day, e.g., twice or more times per day, at a lower dose in immediate release or controlled release forms. While the study data show that an effective plasma concentration can be achieved at about 12-18 hours, e.g., about 15 hours, post treatment with 100 mg/day tradipitant in solid form in immediate release capsules, it will be appreciated that it may be possible to achieve effective plasma concentrations using different doses and/or different formulations, including but not limited to controlled release formulations.

[0030] In conclusion, while the study failed to show an overall effect of the predefined dose of tradipitant for this study, primarily due to the large placebo effect, the study demonstrated a PK-response relationship as well as significant benefits in the group of patients that were evaluated at the time of higher blood concentrations of tradipitant. In this study tradipitant 100 mg qd was well-tolerated and the adverse event profile was mild and similar to placebo.

[0031] Treatment of a patient can be continued until the patient's symptoms of pruritus are ameliorated or eliminated, e.g., ameliorated such that the patient is able to function more or less normally during wake time hours and sleep more or less normally during sleep time hours.

[0032] As discussed above, data indicate that in patients suffering pruritus, e.g., pruritus associated with atopic dermatitis, patients can be treated by orally administering tradipitant. Further studies have demonstrated the safety and efficacy of various dosing regimens.

EXAMPLE 2



[0033] In one study, healthy subject participants were orally administered 85 mg tradipitant on study day 3, and then 85 mg tradipitant Q12H on study days 4-16. Plasma concentration levels of tradipitant were measured on each of day 3, day 7, and day 11.

[0034] This study illustrated that administration of 85 mg tradipitant qd (on day 3) produced an average plasma concentration over hours 0-12 that was about 50% of the plasma concentration observed in the PM group in Example 1. On days 7 and 11, the average plasma concentration over hours 0-12 following administration of 85 mg bid (specifically, Q12H) tradipitant was about 150% of the plasma concentration observed in the PM group in Example 1. The average plasma concentration over hours 0-12 at each point was determined by dividing the AUC for hours 0-12 (in (hr.) x (ng/mL)) by 12 hours.

[0035] These results indicate that in patients suffering pruritus, e.g., pruritus associated with atopic dermatitis, patients can be treated by orally administering tradipitant, e.g., Form IV or Form V (or a pharmaceutically acceptable salt thereof) in an amount of 85 mg bid, e.g., 85 mg Q12H, in order to achieve plasma concentrations that are greater than the 125 ng/mL observed in the PM group in Example 1. .

[0036] From the above, it is apparent that the dose can be one that results in plasma concentration at about 12 hours post-dose of about 100 ng/mL to about 225 ng/mL, including e.g., about 125, about 150, about 175, or about 200 ng/mL.

[0037] Tradipitant can be administered for the treatment of pruritis in an immediate release form at a dose of 50 to 100 mg qd, e.g., 85 mg qd or 100 mg qd. Twice daily (bid) dosing of tradipitant in immediate release forms at 50 to 100 mg allows achievement and maintenance of the target plasma concentrations throughout a 24 hour period. Accordingly, administration of, e.g., 85 mg (immediate release) bid provides greater and/or more sustained relief from the symptoms of pruritis than qd dosing (immediate release) at the same or a higher dose.


Claims

1. Tradipitant for use in treating pruritus and/or atopic dermatitis in an individual by achieving and maintaining a tradipitant plasma concentration of 175 ng/mL or greater throughout a duration of treatment in the individual being treated, such use comprising:
internal administration to the individual of tradipitant in an amount of 170 mg/day.
 
2. Tradipitant for use according to claim 1, wherein the amount of 170 mg/day is 85 mg bid.
 
3. Tradipitant for use in treating pruritus and/or atopic dermatitis in an individual, such use comprising:
internal administration to the individual 170 mg/day of tradipitant the amount and frequency sufficient to achieve and maintain a tradipitant plasma concentration in the individual of 175 ng/mL or greater throughout a duration of treatment.
 
4. Tradipitant for use according to claim 3, wherein the internal administration to the individual is oral administration.
 
5. Tradipitant for use according to claim 4 in treating chronic pruritus in an individual in need thereof.
 
6. Tradipitant for use according to claim 4 in treating chronic pruritus with atopic dermatitis in an individual in need thereof.
 
7. Tradipant for use according to claim 3, wherein the amount of 170 mg/day is 85 mg bid.
 


Ansprüche

1. Tradipitant zur Verwendung bei der Behandlung von Pruritus und/oder atopischer Dermatitis bei einem Individuum durch Erreichen und Aufrechterhalten einer Tradipitant-Plasmakonzentration von 175 ng/mL oder mehr über eine Behandlungsdauer in dem behandelten Individuum, wobei eine derartige Verwendung Folgendes umfasst:
interne Verabreichung von Tradipitant an das Individuum in einer Menge von 170 mg/Tag.
 
2. Tradipitant zur Verwendung nach Anspruch 1, wobei es sich bei der Menge von 170 mg/Tag um 85 mg zweimal pro Tag handelt.
 
3. Tradipitant zur Verwendung bei der Behandlung von Pruritus und/oder atopischer Dermatitis bei einem Individuum, wobei eine derartige Verwendung Folgendes umfasst:
interne Verabreichung von 170 mg/Tag Tradipitant an das Individuum, wobei die Menge und Häufigkeit zum Erreichen und Aufrechterhalten einer Tradipitant-Plasmakonzentration von 175 ng/mL oder mehr über eine Behandlungsdauer in dem Individuum ausreichen.
 
4. Tradipitant zur Verwendung nach Anspruch 3, wobei es sich bei der internen Verabreichung an das Individuum um orale Verabreichung handelt.
 
5. Tradipitant zur Verwendung nach Anspruch 4 bei der Behandlung von chronischem Pruritus bei einem Individuum, bei dem diesbezüglich Bedarf besteht.
 
6. Tradipitant zur Verwendung nach Anspruch 4 bei der Behandlung von chronischem Pruritus mit atopischer Dermatitis bei einem Individuum, bei dem dies bezüglich Bedarf besteht.
 
7. Tradipitant zur Verwendung nach Anspruch 3, wobei es sich bei der Menge von 170 mg/Tag um 85 mg zweimal pro Tag handelt.
 


Revendications

1. Tradipitant pour une utilisation dans le traitement du prurit et/ou de la dermatite atopique chez un individu en atteignant et en maintenant une concentration plasmatique de tradipitant de 175 ng/mL ou plus pendant l'entièreté d'une durée de traitement chez l'individu traité, une telle utilisation comprenant :
une administration interne à l'individu de tradipitant en une quantité de 170 mg/jour.
 
2. Tradipitant pour une utilisation selon la revendication 1, la quantité de 170 mg/jour étant de 85 mg deux fois par jour.
 
3. Tradipitant pour une utilisation dans le traitement du prurit et/ou de la dermatite atopique chez un individu, une telle utilisation comprenant :
une administration interne à l'individu de 170 mg/jour de tradipitant, la quantité et la fréquence étant suffisantes pour atteindre et maintenir une concentration plasmatique de tradipitant chez l'individu de 175 ng/mL ou plus pendant l'entièreté d'une durée de traitement.
 
4. Tradipitant pour une utilisation selon la revendication 3, l'administration interne à l'individu étant par administration orale.
 
5. Tradipitant pour une utilisation selon la revendication 4 dans le traitement du prurit chronique chez un individu qui en a besoin.
 
6. Tradipitant pour une utilisation selon la revendication 4 dans le traitement du prurit chronique avec dermatite atopique chez un individu qui en a besoin.
 
7. Tradipitant pour une utilisation selon la revendication 3, la quantité de 170 mg/jour étant de 85 mg deux fois par jour.
 




Drawing











Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description




Non-patent literature cited in the description