WO2023031114A1

WO2023031114A1 - New therapeutic application of vortioxetine based on the group of patients to be treated

Info

Publication number: WO2023031114A1
Application number: PCT/EP2022/073940
Authority: WO
Inventors: Anne-Cecile V. Bayne; Igor Bendik; Hubert Paul HUG; Giorgio LA FATA; Araksya TOPCHYAN
Original assignee: Dsm Ip Assets B.V.
Priority date: 2021-08-31
Filing date: 2022-08-29
Publication date: 2023-03-09

Abstract

The present invention is about a personalised healthcare invention. The inventors have found that there is a functional relationship between a patient´s vitamin D level and his responsiveness to a treatment with vortioxetine. One embodiment of the invention relates to vortioxetine for use in the treatment of a depressive patient who has a healthy vitamin D level. The present invention also relates to a method of purposively selecting patients for treatment with vortioxetine or a pharmaceutically acceptable salt thereof, wherein the concentration of calcifediol is measured ex vivo in blood samples of patients that are suffering from depression, anxiety and/or chronic pain. The preferred vortioxetine is vortioxetine hydrobromide or any other pharmaceutically acceptable salt thereof.

Description

New therapeutic application of vortioxetine based on the group of patients to be treated

Technical field

The present invention relates to personalized medicine. It also relates to the treatment of patients suffering from major depressive disorder (MDD).

Background of the invention

Trintellix® is an FDA approved medical drug comprising vortioxetine hydrobromide. Commercially available Trintellix® tablets comprise 5 mg, 10 mg, 15 mg, or 20 mg vortioxetine (as hydrobromide). Trintellix® is mostly used for treatment of depression. In some European countries, a corresponding product is or was available as Brintellix®. Similar to Trintellix®, Brintellix® can only be obtained with a prescription and is available as tablets (5, 10, 15 and 20 mg) and oral drops (20 mg/ml). The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness, and sexual dysfunction.

To study mood, depression and anxiety in rats or mice, several behavioral assays have been developed. The forced swim test (FST) measures the presence of or reduction in positive coping skills in rats and mice. When animals are treated with an effective anti-depressant prior to the test, they show reduced immobility and more climbing, suggesting that the animals do not give up, while untreated animals show increased immobility and will float more in the water. Therefore, reduced immobility and more climbing is thought to be an anti-depressive, positive coping phenotype in the FST. Guilloux et al. (2013) have found that vortioxetine (2.5-5 mg/kg) increased mobility in the FST [see Guilloux, J. P. et al., “Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice”, Neuropharmacology, 73, 147-159, 2013],

The German G-BA (“Gemeinsamer Bundesauschuss”) evaluates the additional benefit of drugs with new active ingredients compared to a comparative therapy. Such benefit assessment is done in accordance with Section 35a of the German Social Code, Book V (known as the AMNOG procedure). The result of this benefit assessment is the starting point for price negotiations between the National Association of Statutory Health Insurance Funds (“GKV- Spitzenverband”) and the pharmaceutical manufacturer. At the end of the negotiations, it is determined how much the statutory health insurance will pay for the drug in the future.

In Germany, the benefit assessment of vortioxetine has been rather negative. As a result, the originator company appears to have withdrawn Brintellix® from the German market. Therapeutic options vary in cost along with probability of success and convenience. There is a need to improve the current manner how patients suffering from major depressive disorder (MDD) are being treated.

Summary of the invention

The present invention is about a personalised healthcare invention. It relates to the use of vortioxetine in the treatment of the same or a similar disease(s), but for a particular group of subjects.

Hitherto, every vortioxetine patient has been treated in the same manner - regardless of his or her vitamin D status. However, to be effective, vortioxetine requires a certain amount of vitamin D in the body of the patient.

Patients who lack vitamin D are more likely to not sufficiently respond to a vortioxetine treatment. This is relevant because therapeutic options with a low(er) probability of success should be avoided. This is particularly true if for the same disease, alternative therapeutics options are available.

When comparing vortioxetine to a comparative therapy, patients lacking vitamin D (e.g., vitamin D deficient patients) should be excluded for the study. Such additional exclusion criterion will increase the additional benefit of vortioxetine in the respective assessment study.

The herein disclosed, novel therapeutic application is characterized by a disease (preferably major depressive disorder) and the patients to be treated or not to be treated.

A healthy vitamin D level is a necessary requirement for being a vortioxetine high-responder. Vortioxetine patients having a calcifediol blood concentration of preferably more than 50 nmol/L, or more preferably more than 75 nmol/L are a group of subjects that is distinguished from other groups by its physiological status. Purposive selection of patients is a technical feature that must be taken into account when assessing novelty of a claimed invention.

One embodiment of the present invention relates to a method of purposively selecting (or of purposively disregarding) patients for treatment with vortioxetine or a pharmaceutically acceptable salt thereof, wherein the concentration of calcifediol is measured ex vivo in blood samples of patients that are suffering from depression, anxiety and/or chronic pain.

The inventors have found a functional relationship between a biomarker (calcifediol blood concentration) and responsiveness to treatment with vortioxetine. One embodiment of the invention relates to vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient who has a healthy vitamin D level (i.e., who is not in need of vitamin D supplementation).

A preferred embodiment of the invention relates to vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient whose calcifediol blood concentration that is higher than 50 nmol/L, or is preferably higher than 75 nmol/L.

Subject-matter relating to purposively selected patients for treatment with a known drug is novel over the prior art treatment, even in case of an overlapping patient group with the same drug.

Figures

Figures 1 and 2 relate to Example 1 (vide infra). FIGURE 1 shows a lack of effects of acute vortioxetine treatment in the forced swim test (FST) in male Balb/cJ mice that were vitamin D deficient. Vortioxetine was dosed at 5 mg/kg bw at 24, 6 and 1 hours before the FST. The immobility time in seconds [s] is shown and is expressed as means ± SE (standard error). The experiment duration was 6 minutes. In the control group, a vehicle was applied. Surprisingly, vortioxetine had no positive effect in vitamin D deficient mice. Despite of vortioxetine treatment, immobility time was about as long as in the control group.

Figure 2 shows the effects of vitamin D supplementation in the forced swim test (FST) in male Balb/cJ mice that were treated with vortioxetine. Vortioxetine (5 mg/kg bw) alone or in combination with vitamin D at 0.05 (low) or 0.10 (high) mg/kg bw was given at 24, 6 and 1 hours prior to the FST. The immobility time was recorded and the data in seconds [s] is expressed as means ± SE (standard error). The experiment duration was 6 minutes. Significance (*) of p< 0.05 was tested using one-way RM ANOVA with Tukey’s post-hoc analysis. Figure 2 shows that in vitamin D deficient mice, vortioxetine shows positive effect if vitamin D is coadministered.

Figures 3 and 4 relate to Example 2 (vide infra). Figure 3 shows a lack of effects of acute vortioxetine treatment on cerebral blood flow (CBF) in male Balb/cJ mice that were vitamin D deficient. Vortioxetine was dosed at 5 mg/kg bw at 24, 6 and 1 hours before the CBF. In the control group, a vehicle was applied. The mean percentage above baseline ± SE (standard error) is shown. Trial time post dipyridamole injection lasted for 10 minutes. It is surprising that vortioxetine has no effect on CBF in vitamin D deficient mice.

Figure 4 shows effects of acute vortioxetine treatment in combination with different doses of vitamin D on cerebral blood flow (CBF) in male Balb/cJ mice that were vitamin D deficient. Vortioxetine (5 mg/kg bw) alone or in combination with vitamin D at 0.05 (low) or 0.10 (high) mg/kg bw was given at 24, 6 and 1 hours prior to the CBF measurement. The mean percentage above baseline ± SE (standard error) is shown. Trial time post dipyridamole injection lasted for 10 minutes. Significance (*) of p<0.05 was tested using one-way RM ANOVA with Tukey’s post- hoc analysis. Figure 4 shows that in vitamin D deficient mice, vortioxetine has only an effect on CBF if vitamin D is co-administered.

Figure 5 relates to Example 3 (vide infra) and shows effects of acute vortioxetine treatment in the forced swim test (FST) in male Balb/cJ mice that were vitamin D deficient. Vortioxetine (5 mg/kg bw) alone or in combination with calcifediol at 0.025 mg/kg bw was given at 24, 6 and 1 hours prior to the FST. The immobility time was recorded and the data in seconds [s] is expressed as means ± SE (standard error). The experiment duration was 6 minutes. Significance (*) of p< 0.05 was tested using one-way RM ANOVA with Tukey’s post-hoc analysis. A comparison of Figure 5 with Figure 2 shows that a low dosage of the selected vitamin D metabolite (calcifediol) is as effective as a high dosage of vitamin D3.

Figure 6 relates to Example 3 (vide infra) and shows effects of acute vortioxetine treatment in combination with different doses of vitamin D on cerebral blood flow (CBF) in male Balb/cJ mice that were vitamin D deficient. Vortioxetine (5 mg/kg bw) alone or in combination with vitamin D at 0.05 or 0.10 mg/kg bw, or in combination with calcifediol at 0.025 or 0.050 mg/kg bw, was given at 24, 6 and 1 hours prior to the CBF measurement. The mean percentage above baseline ± SE (standard error) is shown. Trial time post dipyridamole injection lasted for 10 minutes. Significance (*) of p<0.05 was tested using one-way RM ANOVA with Tukey’s post-hoc analysis.

Detailed description of the invention

The inventors have unveiled a reason for a poor response to vortioxetine treatment: lack of vitamin D. The surprising interaction of vitamin D and vortioxetine allows to improve various aspects of the current vortioxetine treatment.

It also allows to avoid therapeutic options with low(er) probability of success.

Definitions

In the context of the present invention, the term “vitamin D” refers to any kind of vitamin D, including all vitamers of vitamin D and also including metabolites of vitamers of vitamin D. A vitamin D metabolite is thereby a molecule that is either a precursor, an intermediate or the final, physiologically modified product of the vitamin D pathway in the human body. Thus, in the context of the present invention, the term “vitamin D” is to be understood in a very broad manner. Preferably, the term “vitamin D” refers to D3 (cholecalciferol), vitamin D2 (ergocalciferol), to a vitamin D metabolite or a mixture thereof. More preferably, the term “vitamin D” refers to vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol) or a mixture thereof. The most preferred vitamin D metabolite is calcifediol (25-hydroxyvitamin D3, also referred to as "25-OH D3"). When measuring the vitamin D level of a patient, it is common to measure the concentration calcifediol in a sample of the patient. Other vitamin D metabolites are 1 -alpha, 25-vitamin D3 and 1 -alpha, 25-vitamin D2.

For human beings, vitamin D is essential. In that sense, everybody needs vitamin D. However, this is not what is meant by the expression “in need of vitamin D”. A patient who is “in need of vitamin D” is a patient whose vitamin D level is below the recommendation limit of a governmental or non-governmental medical organization. The recommendation limit of the Institute of Medicine (IOM) is 50 nmol calcifediol per liter blood. The recommendation limit the medical ‘Endocrine Society’ association is 75 nmol calcifediol per liter blood.

In the context of the present invention, a patient is “in need of vitamin D supplementation” if he or she has a calcifediol blood concentration lower than 75 nmol/L, preferably lower 50 nmol/L, more preferably lower than 45 nmol/L, even more preferably lower than 40 nmol/L and most preferably lower than 35 nmol/L. A patient, whose vitamin D level is in a healthy range is not in need of vitamin D supplementation. A patient, whose calcifediol blood concentration is 75 nmol/L or more is not in need of vitamin D supplementation.

A patient who is “vitamin D insufficient” has a calcifediol blood concentration preferably lower than 50 nmol/L. A patient who is “vitamin D deficient” has a calcifediol blood concentration preferably lower than 30 nmol/L. In case of a calcifediol blood concentration lower than 10 nmol/L, the patient is severely vitamin D deficient.

In the context of the present invention, the term “vortioxetine” refers to vortioxetine or a pharmaceutically acceptable salt thereof. Thus, the term “vortioxetine” is to be understood in a broad manner. Preferably, the term “vortioxetine” refers to a pharmaceutically acceptable salt of vortioxetine. Most preferably, the term “vortioxetine” refers to vortioxetine hydrobromide.

A “kit” is a set of articles or equipment needed for a specific purpose. The preferred kit of the invention comprises the herein described composition and means for measuring the vitamin D level of a patient.

A “patient” is a human subject who is in need of medical advice and/or is suffering from a disease. In the context of the present invention, a “patient” is preferably a human subject that is in need of pharmaceutical drug. More preferably, it is a human subject that is in need of vortioxetine or a pharmaceutically acceptable salt thereof.

A “vortioxetine non-responder” is a patient who is in need of antidepressant treatment but shows no positive response to the vortioxetine treatment. Preferably, “no positive response to vortioxetine treatment” means that a daily dosage of 20 mg vortioxetine (as hydrobromide) does not relieve the patient's symptoms. A “vortioxetine low-responder” is a patient who is in need of antidepressant treatment but shows poor response to the vortioxetine treatment. Preferably, “poor response to vortioxetine treatment” means that a daily dosage of 10 mg or 15 mg vortioxetine (as hydrobromide) does not relieve the patient's symptoms. Vortioxetine non-responders may also be considered as vortioxetine low-responders. However, not every vortioxetine low-responder is necessarily also a vortioxetine non-responder. A not sufficient vitamin D level is believed to be a reason for being a vortioxetine non-responder or a vortioxetine low-responder.

In some situations, patients that are neither vortioxetine non-responders nor vortioxetine low-responders may be summarized as “vortioxetine higher-responder”. In other situations, a vortioxetine higher-responder is a patient that responds particularly well to vortioxetine or a pharmaceutically acceptable salt thereof.

Vitamin D

The herein disclosed pharmaceutical combination comprises vitamin D. Several kinds (vitamers) of vitamin D exist. The two major vitamers are vitamin D3 and vitamin D2. Thus, a preferred pharmaceutical combination of the present invention comprises vitamin D3, vitamin D2 or a mixture thereof. In the context of the present invention, there is no reason for mixing vitamin D3 with vitamin D2. Thus, more preferably, the pharmaceutical combination of the present invention comprises either vitamin D3 or vitamin D2, but not a mixture thereof.

Calcifediol is a vitamin D metabolite, more specifically a vitamin D3 metabolite. In the human body, calcifediol is the most abundant metabolite of vitamin D. When determining a patient's vitamin D level, it is common to measure the concentration of calcifediol directly or indirectly in a sample of the patient's blood. When orally administered, calcifediol has excellent bioavailability and hence, is very well absorbed by the body. This helps reaching optimal vitamin D levels faster. Thus, in an also preferred embodiment, the pharmaceutical combination of the present invention comprises at least one vitamin D metabolite, preferably at least one vitamin D3 metabolite and most preferably calcifediol.

Calcifediol for human consumption is commercially available as ampli-D® (DSM® Nutritional Products, Switzerland). Calcifediol is also available as Rayladee® (OPKO Health, Miami, FL) and as Hidroferol® oral solution (Faes Farma, S.A., Spain). Without wishing to be bound by theory, it is believed that calcifediol is improving vortioxetine treatment more effectively because a metabolic step can be skipped in the patient's body: whereas most kinds of vitamin D first need to be hydroxylated in the liver at position 25, this is not needed if calcifediol is administered.

Vortioxetine

The herein disclosed pharmaceutical combination comprises vortioxetine. Several kinds of vortioxetine exist, including pharmaceutically acceptable salts of vortioxetine. Most if not all commercially available products comprise a pharmaceutically acceptable salt of vortioxetine. Commercially available, solid mono-preparations comprise vortioxetine hydrobromide.

The purpose of the present invention is to improve existing vortioxetine treatments. In consideration thereof, pharmaceutically acceptable salts of vortioxetine are preferred. Vortioxetine hydrobromide is the most preferred pharmaceutically acceptable salt of vortioxetine.

However, in the special case of liquid oral dosage forms, vortioxetine (D.L)-lactate is the preferred pharmaceutically acceptable salt of vortioxetine. Brintellix® solution (oral drops, 20 mg/ml) is a commercially available liquid oral dosage form of vortioxetine. Each drop contains vortioxetine (D.L)-lactate equivalent to 1 mg vortioxetine. Thus, in case of a liquid oral dosage form of vortioxetine, vortioxetine (D.L)-lactate is the preferred pharmaceutically acceptable salt of vortioxetine.

Composition for use of the invention

The present invention relates to a novel use of a composition that comprises vortioxetine or a pharmaceutically acceptable salt thereof.

Typically, the composition for use according to the invention is a pharmaceutical composition. Pharmaceutical compositions are suitable for human consumption. Most often, pharmaceutical compositions comprise at least one pharmaceutically acceptable excipient. Some examples of materials which can serve as pharmaceutically acceptable excipient include: liquid carriers (such as water, ethanol, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and phosphate buffer solutions), sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, fat and oils (such as cocoa butter, waxes, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol), polyols (such as glycerin, sorbitol, mannitol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid and other non-toxic materials employed in pharmaceutical formulations.

In a preferred embodiment, the composition for use according to the invention is an oral dosage form and is more preferably a solid oral dosage form or a liquid oral dosage form.

In case of a liquid oral dosage form, the composition for use according to the invention comprises preferably at least one pharmaceutically acceptable salt of vortioxetine, comprises more preferably vortioxetine lactate, and comprises most preferably vortioxetine (D,L)-lactate. Preferred pharmaceutically acceptable excipients for liquid oral dosage forms are liquid carriers such as water, ethanol, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and phosphate buffer solutions. In a preferred embodiment, the composition for use according to the invention is a liquid oral dosage form which comprises vortioxetine (D.L)-lactate and at least one pharmaceutically acceptable excipient. More preferably, the composition for use according to the invention is a solution which comprises vortioxetine (D.L)-lactate and ethanol.

An even more preferred composition for use according to the invention is a liquid oral dosage form comprising: vortioxetine (D.L)-lactate; and at least one pharmaceutically acceptable excipient, wherein such liquid dosage form is preferably a solution which comprises preferably 15-25 mg vortioxetine (D.L)-lactate per ml solution, and wherein such liquid oral dosage form preferably comprises ethanol.

In case of a solid oral dosage form, the composition for use according to the invention comprises preferably at least pharmaceutically acceptable salt of vortioxetine, and comprises more preferably vortioxetine hydrobromide. Preferred solid oral dosage forms are powders, granules, pills, capsules and tablets. In a preferred embodiment, the composition for use according to the invention is a tablet that comprises vortioxetine hydrobromide and at least one pharmaceutically acceptable excipient, and is more preferably a film coated tablet that comprises vortioxetine hydrobromide and at least one pharmaceutically acceptable excipient. In case of a solid oral dosage form, the composition for use according to the invention comprises preferably mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide and/or iron oxide red. These pharmaceutically acceptable excipients are particularly preferred in case the composition for use according to the invention is a film coated tablet.

Commercially available solid oral dosage forms comprise 5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide. The purpose of the present invention relates a novel use of existing vortioxetine medication. Therefore, in case of a solid oral dosage form, the composition for use according to the invention preferably also comprises 5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide.

A preferred composition for use according to the invention is a solid oral dosage form comprising:

5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide; and at least one pharmaceutically acceptable excipient, wherein such solid dosage form is preferably a tablet and is more preferably a film coated tablet, and wherein such solid oral dosage form comprises preferably mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide and/or iron oxide red.

Novel use of a vitamin D measurement device

Hitherto, it was not possible to predict whether a patient will be a vortioxetine high-responder, vortioxetine low-responder or a vortioxetine non-responder. This is now changing. The inventors have found a functional relationship between a biomarker (calcifediol blood concentration) and responsiveness to treatment with vortioxetine.

The present invention is about of purposively selecting (or purposively disregarding) patients for treatment with vortioxetine. To do so, the vitamin D level of patients that are in need of vortioxetine is preferably measured.

A preferred embodiment of the invention is a method of purposively selecting or of purposively disregarding patients for treatment with vortioxetine or a pharmaceutically acceptable salt thereof, wherein the concentration of calcifediol is measured ex vivo in blood samples of patients that are in need of vortioxetine (e.g., in blood samples of patients that are suffering from depression, anxiety and/or chronic pain). Thereby, patients having a calcifediol blood concentration that is lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L, even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L are preferably not selected. For patients have such low vitamin D level, serotonin modulators other than vortioxetine are available (i.e., an alternative therapeutic option with higher probability of success is recommended).

Measurement devices suitable for measuring vitamin D levels are well known and also commercially available. In the context of the present invention, such measurement devices are used for assessing the benefit of the herein described composition for a predetermined patient. Such approach is particularly meaningful if vortioxetine treatment of said predetermined patient has not yet been initiated or is about be re-initiated.

To determine the vitamin D level of a patient, it is preferred to measure (directly or indirectly) the patient's calcifediol blood concentration. Preferably, said measurement is done ex vivo in a blood sample of the patient. One embodiment of the present invention relates to the use of a measurement device for assessing the benefit of the herein described composition, wherein the benefit for a predetermined patient is assessed, and wherein said measurement device is suitable for measuring ex vivo the concentration of calcifediol in a blood sample of said predetermined patient, and wherein said predetermined patient is suffering from depression, anxiety and/or chronic pain, or is suffering from depression and from at least one cerebrovascular disease, or is suffering from depression that is associated with cerebrovascular atherosclerosis.

Also disclosed is a method of identifying patients that are likely to be vortioxetine low-responders or vortioxetine non-responders, characterized in that a device is used which is suitable for measuring ex vivo the concentration of calcifediol in a blood sample. An alternative a method relates to the identification patients that are unlikely to be vortioxetine high-responders, characterized in that a device is used which is suitable for measuring ex vivo the concentration of calcifediol in a blood sample.

Some vitamin D measurement devices are relatively small and cheap. They may therefore be included in a kit. One embodiment of the invention relates to a kit that comprises the herein disclosed composition and means facilitating the ex vivo measurement of calcifediol in a blood sample, wherein said means is preferably a device for measuring ex vivo the concentration of calcifediol in a blood sample. Some parts of the device may be reusable, whereas other parts may be expendable material that is consumed when running the device. Parts that are reusable do not need to be included in each and every kit. Therefore, a preferred kit of the invention comprises means facilitating the ex vivo measurement of calcifediol in a blood sample, wherein said means are preferably expendable materials that are consumed when running a device for measuring ex vivo the concentration of calcifediol in a blood sample.

Medical use

The inventors have found that the presence of vitamin D is necessary for vortioxetine to exert its effects. Patients having a suboptimal level of vitamin D in their blood (i.e., are in need of vitamin D supplementation) should therefore not be treated with vortioxetine. Indeed, alternative drugs for the treatment of MDD are available (e.g., other serotonin modulators).

When excluding patients that are in need of vitamin D supplementation, much less vortioxetine non-responders and low-responders will be observed. This is in the interest of the patient and the public: patients are better treated and money is not spent for therapies with little benefit for the patient.

One embodiment of the present invention relates to a composition comprising vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient who is suffering from depression, anxiety and/or chronic pain, or characterized in that said patient is not vitamin D deficient, or characterized in that said patient is neither vitamin D deficient nor vitamin D insufficient, or characterized in that said patient has a calcifediol blood concentration of at least 50 nmol/L or preferably at least 75 nmol/L.

A preferred embodiment of the present invention relates to a composition comprising vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient who is suffering from major depressive disorder, characterized in that said patient is not vitamin D deficient, or characterized in that said patient is neither vitamin D deficient nor vitamin D insufficient, or characterized in that said patient has a calcifediol blood concentration of at least 50 nmol/L or preferably at least 75 nmol/L.

An even more preferred embodiment of the present invention relates to a composition comprising vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient from depression and from at least one cerebrovascular disease, and wherein said patient is preferably suffering from depression that is associated with cerebrovascular atherosclerosis, characterized in that said patient is not vitamin D deficient, or characterized in that said patient is neither vitamin D deficient nor vitamin D insufficient, or characterized in that said patient has a calcifediol blood concentration of at least 50 nmol/L or preferably at least 75 nmol/L.

In these embodiments, the above-mentioned preferences apply. Thus, the compositions are preferably oral dosage forms which comprise in addition to the active pharmaceutical ingredient (i.e., vortioxetine or a pharmaceutically acceptable salt thereof) at least one pharmaceutically acceptable excipient. Regarding preferred pharmaceutically acceptable excipients, the above- mentioned preferences are again applicable.

A particularly preferred embodiment of the present invention relates to a solid oral dosage form for use in the treatment of a patient who is suffering from major depressive disorder, wherein said solid oral dosage form is preferably a film coated tablet comprising:

5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide; and at least one pharmaceutically acceptable excipient selected from the group consisting of mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide and iron oxide red, characterized in that said patient is not vitamin D deficient, or characterized in that said patient is neither vitamin D deficient nor vitamin D insufficient, or characterized in that said patient has a calcifediol blood concentration of at least 50 nmol/L or preferably at least 75 nmol/L.

An also particularly preferred embodiment of the present invention relates to a liquid oral dosage form for use in the treatment of a patient who is suffering from major depressive disorder, wherein said liquid oral dosage form comprises vortioxetine (D,L)-lactate, and wherein said liquid oral dosage form is preferably a solution which comprises preferably 15-25 mg vortioxetine (D.L)-lactate per ml solution, and wherein said liquid oral dosage form is more preferably an ethanolic solution which comprises preferably 15-25 mg vortioxetine (D.L)-lactate per ml solution. It goes without saying that the above two particularly preferred embodiments are not limited for use in the treatment of a patient who is suffering from major depressive disorder. Thus, the above two particularly preferred embodiments are also for use in the treatment of a patient who is suffering from depression, anxiety and/or chronic pain, and are also for use in the treatment of a patient who is suffering from depression and from at least one cerebrovascular disease, and are also for use in the treatment of a patient who is suffering from depression that is associated with cerebrovascular atherosclerosis.

A use in the treatment of a patient who is suffering from depression that is associated with cerebrovascular atherosclerosis is novel and surprising.

Cerebral blood flow (CBF) is the blood supply to the brain in a given period of time. In a human adult, CBF is typically 750 millilitres per minute or 15% of the cardiac output. Cerebral blood flow is determined by a number of factors, such as viscosity of blood, how dilated blood vessels are, and the net pressure of the flow of blood into the brain, known as cerebral perfusion pressure, which is determined by the body's blood pressure. When treating such patient with the pharmaceutical combination of the present invention, the patient's cerebral blood flow (CBF) is increased. This suggests that abnormal cerebral blood flow is associated with a patient's lower or poor responsiveness to a vortioxetine treatment.

A suboptimal cerebral blood flow is associated with several cerebrovascular diseases such as cerebrovascular atherosclerosis. In fact, depression and cerebrovascular atherosclerosis often occur in comorbidity showing neuropsychological impairment and poor response to antidepressant treatment. Therefore, one embodiment of the present invention relates to the composition of the present invention for use in the treatment of a patient suffering from major depressive disorder (MDD), wherein said patient has a suboptimal cerebral blood flow.

A further embodiment of the present invention relates to an oral dosage form comprising at least one pharmaceutically acceptable excipient and vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient who is suffering from depression that is associated with cerebrovascular atherosclerosis, wherein said oral dosage form is preferably the herein described solid or liquid oral dosage form, and characterized in that said patient is not vitamin D deficient, or characterized in that said patient is neither vitamin D deficient nor vitamin D insufficient, or characterized in that said patient has a calcifediol blood concentration of at least 50 nmol/L or preferably at least 75 nmol/L. Examples

In below Examples 1 to 4, the following materials and methods were used:

Test Article Identification and Preparation. Pre-formulated diets lacking vitamin D (Modified AIN-93G Rodent Diet with no added vitamin D3: Research Diets, New Brunswick, NJ; catalogue No. D10073001 , lot No. 20090401) was shipped ambient and stored at -20°C prior to use. ROVIMIX® Hy-D® 1.25% (Hy-D is calcifediol, DSM Nutritional Products, Lot No. WB01990008) and dry Vitamin D3 100 CWS/AM (DSM Nutritional Products, lot No. UT19010007) were prepared for PO dosing at 10 mL/kg in vehicle (1 % fish gelatin in PBS). ROVIMIX® Hy-D® 1 .25% is a formulation comprising 1 .25 weight-% 25-Hydroxy-vitamin D3, based on the total weight of the formulation. Vortioxetine (Advanced Chemblock Inc., Cat. P50895, CAS 960203-27-4, Batch 19394) was prepared in for PO (per os) dosing at 10 mL/kg in vehicle. The purchased vortioxetine is vortioxetine hydrobromide. Thus, in the context of the examples, “vortioxetine” refers to vortioxetine hydrobromide. The vehicle for mock PO dosing of the test articles was sterile saline. Dipyridamole was used for induction of vasodilation during the assays of cerebral blood flow. Dipyridamole (Millipore-Sigma, catalog No. D9766; Lot No. BCCB0805) was prepared fresh in a 20% b-cyclodextrin solution in sterile water (VetOne, lot No. A1806022) on study days 64 through 67 for intraperitoneal (IP) injection at 1 mL/kg.

Test System Identification. Male Balb/cJ mice (N = 96; stock number 000651) were obtained from The Jackson Laboratory (Bar Harbor, ME). The mice were 4 weeks old and weighed approximately 17 to 22 grams (mean of 20.2 g) at enrollment on study day 0. The animals were identified by marks at the base of tail delineating animal number. After randomization, all cages were labeled with protocol number, group number, and animal numbers.

Environment and Husbandry. Upon arrival, the animals were housed 3 per cage in polycarbonate cages with wire tops, wood chip bedding, and suspended food and water bottles. The mice were housed either in shoebox cages (static airflow, approximately 0.045 m2 floor space) with filter tops or in individually ventilated pie cages (passive airflow, approximately 0.045-0.048 m2 floor space). An attending veterinarian was on site or on call during the live phase of the study. No concurrent medications were given.

The animals were acclimated for 7 days prior to being placed in the study. During the acclimation and study periods, the animals were housed in a laboratory environment with temperatures ranging 19°C to 25°C and relative humidity of 30% to 70%. Automatic timers provided 12 hours of light and 12 hours of dark. Animals were allowed access ad libitum to Envigo Teklad 8640 diet or vitamin D-deficient diet and fresh municipal tap water.

Animal care including room, cage, and equipment sanitation conformed to the guidelines cited in the Guide for the Care and Use of Laboratory Animals and the applicable SOPs. Experimental Design. The animals were given immediate ad libitum access to water and standard rodent chow and acclimated to the facility for 7 days prior to any further intervention. After 7 days of acclimatization, the animals were randomized by weight, placed on chow deficient in vitamin D, and subjected to mock oral gavage on a twice-weekly basis for 6 weeks. For behavioral testing the study was divided into 4 cohorts of 24 animals each (3 mice/group per cohort) with dosing and testing of each cohort proceeding on successive days. The mice were dosed by oral gavage 24, 6, and 1 hour prior to behavioral testing.

Example 1. Vortioxetine alone is not effective in vitamin D deficient animals. A combination of vitamin D and vortioxetine is needed for anti-depressive effects in the forced swim test.

The forced swim test (FST) is a test centered on a rodent’s response to unescapable stress. Results of this test have been interpreted as a measure of susceptibility to negative mood. It is used to measure the effectiveness of antidepressants. Forced swim tests were performed in groups of 12 mice, per treatment. We provided the substances to the animals per gavage at 24, 6 and 1 hours before the FST. The animals were acclimated to the testing room for 1 hour prior to testing. Four animals were tested simultaneously. The animals were each placed in a plexiglass cylindrical container (45 cm x 20 cm; Stoelting Co., Wood Dale, IL) filled with fresh water (25- 27°C) to 30 cm above the bottom. The animals remained in the containers for 6 minutes and were monitored by a computer program with tracking software (Ethovision, Noldus). The mice were observed constantly to mitigate the outside chance that an animal drowned or began to drown (i.e., spent more than 5 seconds completely submerged). After 6 minutes, the animals were removed, towel-dried, and returned to their holding cages. The chambers were drained and cleaned with 70% ethanol then refilled between tests. The animals were returned to their home cage and room after all of the animals in the cohort were tested. All videos were checked and threshold-ed post-hoc by an experimenter blind to the group assignments. Total time swimming or immobile was then acquired via computer-driven video analysis. Swimming was defined as movement of the forelimbs and hind limbs that did not break the surface of the water. Immobility was defined as absence of any movement except for slight movements necessary for the animal to keep its head above water. Data was statistically analyzed using the GraphPad Prism software (San Diego, CA, USA).

Surprisingly, it was observed that in the forced swim test (FST) vitamin D deficient mice treated with vortioxetine did not differ from the vehicle control group as shown in Figure 1 . This result of Example 1 differs from those of Guilloux et al. (2013) in which vortioxetine (5 mg/kg) increased the time in mobility in the FST. In contrast to the animals of Example 1 , the animals of Guilloux et al. (2013) were not vitamin D deficient. This suggests that the presence of vitamin D might be necessary for vortioxetine to exert the effects. We tested this hypothesis by combining vortioxetine with vitamin D at two different doses. Interestingly, in the acute FST depression model we could show that the combination of vortioxetine together with a sufficient dose of vitamin D improved the depression scores. In Figure 2, mice having sufficient vitamin D in the vortioxetine combination (vortioxetine_D2_high) showed reduced immobility scores.

Example 1 shows the benefit of administering vortioxetine together with vitamin D when treating vitamin D deficient subjects.

Example 2. In vitamin D deficient animals, vortioxetine showed an improvement in cerebral blood flow only in combination with vitamin D

For the cerebral blood flow (CBF) measurement, the animals were anesthetized one hour after the last test article administration using 2% isoflurane (VetOne, catalogue No. 502017), and each animal's skull was exposed by a midline scalp incision. The scalp was removed to visualize the brain without disturbing the overlying skull. The animals were then injected (IP) with dipyridamole (DP; 10 mg/kg) and placed in the prone position under the laser Doppler device (MoorLDI2; Moor Instruments, Wilmington, DE). Body temperature was maintained at approximately 30°C with a heating pad, and anesthesia and immobility were maintained with 1 .5% isoflurane. The surface of the brain was diffusely illuminated by a 785-nm laser light. The scattered light was filtered and detected by a digital camera positioned above the animal's head. Raw speckle images were used to compute the speckle contrast, which is a measure related to the number and velocity of moving particles (i.e., CBF). Thirteen, color-coded, blood-flow images were compiled for each animal at 45-second intervals, resulting in CBF monitoring for 10 minutes post-DP injection. The first 5 scans were averaged as baseline CBF, and all subsequent scans were normalized to the baseline as the CBF response to DP.

Interestingly, vortioxetine did not show any significant change in CBF when compared to the control group in vitamin D deficient animals (Figure 3).

It can be assumed that vitamin D deficiency is the explanation why vortioxetine did not exert its effects in the forced swim test (cf. Example 1). Therefore, we were interested to see additional hint in the brain when adding vitamin D to the vortioxetine treatment. And surprisingly, the combination of vortioxetine and vitamin D was effective in the CBF experiment. Interestingly enough, using the CBF methodology, the combined effect of vortioxetine can already be seen at the lower dose of vitamin D (0.05 mg/kg bw) (Figure 4). The observation that cerebral blood flow is improved in the brain of vitamin D deficient subjects by administering vortioxetine in combination with vitamin D is consistent with the results shown in Figure 2.

Example 3. The combination of vortioxetine and calcifediol, a metabolite of vitamin D3, relieved the depressive mood in mice in the forced swim test (FST).

Vortioxetine alone was not effective in ameliorating depressive mood in vitamin D deficient Balb/cJ mice in the forced swim test (cf. Example 1). After having observed the vitamin D effect in vortioxetine treatment (cf. Example 2), we were interested whether other vitamin D metabolites could have a similar action. Therefore, calcifediol (25-hydroxy vitamin D3, 25D3) co-administration was tested in the FST. Intriguingly, a low dose of calcifediol (0.025 mg/kg bw) had the same effect like the high dose of vitamin D3 (0.10 mg/kg bw), when together with vortioxetine to vitamin D deficient mice. Figure 5 shows that the combination of calcifediol with vortioxetine effectively improves the anti-depressive behavior of vitamin D deficient mice in the FST as seen by reducing the immobility per minute.

Example 4. Both combinations, ‘vortioxetine and vitamin D’ and ‘vortioxetine and calcifediol’, improved cerebral blood flow in a dose-depending manner.

Similar to Example 2, calcifediol was tested in two different concentrations (0.025 mg/kg bw; 0.050 mg/kg bw) in combination with vortioxetine in the CBF experiment vitamin D deficient mice. A dose dependent effect was observed. A two times higher oral dose of vitamin D resulted in less improved cerebral blood flow than calcifediol (Figure 6).

The result of Example 4 shows a dose-effect relationship for both, vitamin D and calcifediol.

Example 5a. Mono-therapy; comparison with comparator therapy.

In Example 5a, vortioxetine is compared with another therapy (“comparator therapy”) to assess its added benefit. Both drugs are approved for patient treatment by the drug authorities. They have a positive benefit-risk ratio, i.e. both are effective and safe.

To assess the added benefit, 100 patients are split into two groups. A first group is treated with a vortioxetine, whereas a second group is treated with a comparator therapy. Patient-relevant endpoints (“positive effects") from which the additional benefit is to be derived are defined. An additional benefit is attested if, for example, a significant improvement of disease symptoms or an avoidance of side effects can be shown compared to the comparative therapy. In Example 5a shows that vortioxetine has little added benefit.

Example 5b. Mono-therapy; subjects with low vitamin D level are excluded.

In Example 5b, the assessment of Example 5a is repeated. However, to participate in the assessment, patients must have a healthy vitamin D level (i.e., low vitamin D level is an exclusion criterion).

100 patients that have calcifediol blood concentration of more than 50 nmol/L are split into two groups. A first group is treated with vortioxetine, whereas a second group is treated with a comparator therapy. The same patient-relevant endpoints (“positive effects") as in Example 5a are applied. The duration of the assessment is as long as in Example 5a, but at least 6 months.

In Example 5b, vortioxetine has a significant added benefit.

A comparison of Examples 5a and 5b shows the relevance of a healthy vitamin D level when treating a patient with vortioxetine: to be successful in an AMNOG procedure or any other benefit assessment, patients with low vitamin D level should be excluded.

Example 5c. Combination therapy; low vitamin D subjects receive vitamin D supplementation.

In Example 5c, the assessment of Example 5a is repeated. However, to participate in the assessment, patients must have a low vitamin D level (i.e., normal vitamin D level is an exclusion criterion).

100 patients that have a calcifediol blood concentration of less than 30 nmol/L are split into two groups. A first group is treated with a fixed combination (namely with a solid oral dosage form comprising vortioxetine and calcifediol), whereas a second group is treated with a comparator therapy. The same patient-relevant endpoints (“positive effects") as in Example 5a are applied. The duration of the assessment is as long as in Example 5a, but at least 6 months.

In Example 5c, the combination therapy (vortioxetine + calcifediol) has a significant added benefit.

Examples 5c shows that a low vitamin D level of a patient does not need to be a show stopper. Oral supplementation of vitamin D (via fixed combination) brings the patient's vitamin D level back to normal and thus, makes vortioxetine treatment successful.

Claims

1 . Composition comprising vortioxetine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient who is suffering from depression, anxiety and/or chronic pain, characterized in that said patient is not vitamin D deficient.

2. Composition for use according to claim 1 , wherein said patient is suffering from major depressive disorder.

3. Composition for use according to claim 1 , wherein said patient is suffering from depression and from at least one cerebrovascular disease, and wherein said patient is preferably suffering from depression that is associated with cerebrovascular atherosclerosis.

4. Composition for use according to any one of the preceding claims, wherein said patient does not have a calcifediol blood concentration of less than 10 nmol/L, and wherein said patient is preferably neither vitamin D deficient nor vitamin D insufficient.

5. Composition for use according to any one of the preceding claims, wherein said patient is not in need of vitamin D supplementation, and wherein said patient does preferably not have a calcifediol blood concentration lower than 35 nmol/L.

6. Composition for use according to any one of the preceding claims, wherein said patient has a calcifediol blood concentration of at least 50 nmol/L or of at least 75 nmol/L.

7. Composition for use according to any one of the preceding claims, wherein said composition is an oral dosage form which preferably comprises a pharmaceutically acceptable salt of vortioxetine.

8. Composition for use according to any one of the preceding claims, wherein said composition is a solid oral dosage form which preferably comprises vortioxetine hydrobromide.

9. Composition for use according to any one of the preceding claims, wherein said composition is a solid oral dosage comprising:

5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide; and at least one pharmaceutically acceptable excipient.

10. Composition for use according to any one of the preceding claims, wherein said composition is a film coated tablet comprising:

5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide; and at least one pharmaceutically acceptable excipient select from the group consisting of mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide and iron oxide red.

11 . Composition for use according to any one of claims 1 to 7, wherein said composition is a liquid oral dosage form which preferably comprises vortioxetine (D,L)-lactate.

12. Composition for use according to claim 11 , wherein said composition is a solution which comprises preferably 15-25 mg vortioxetine (D.L)-lactate per ml solution.

13. Composition for use according to claim 11 or 12, wherein said composition further comprises at least one pharmaceutically acceptable excipient that is preferably ethanol.

14. Method of purposively selecting patients for treatment with vortioxetine or a pharmaceutically acceptable salt thereof, wherein the concentration of calcifediol is measured ex vivo in blood samples of patients that are suffering from depression, anxiety and/or chronic pain.

15. Method according to claim 14, wherein patients having a calcifediol blood concentration that is lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L, even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L are not selected.