WO2022055408A1 - Desloratadine or loratadine for use in the treatment of breast cancer - Google Patents
Desloratadine or loratadine for use in the treatment of breast cancer Download PDFInfo
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- desloratadine
- loratadine
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- This invention pertains in general to the field of breast cancer treatment. Furthermore, the invention pertains to a breast cancer treatment that prevents or lessens lung cancer metastasis from breast cancer. More particularly the invention relates to a medicament for breast cancer treatment.
- breast cancer is the most common cancer types for women, and affects one in eight women during their lives.
- Risk factors for breast cancer include, gender, age, genes, personal factors and other risks such as being overweight, using hormone replacement therapy (also called menopausal hormone therapy), taking birth control pills, drinking alcohol, not having children or having your first child after age 35 or having dense breasts.
- hormone replacement therapy also called menopausal hormone therapy
- Symptoms of breast cancer may include a lump in the breast, a change in size or shape of the breast or discharge from a nipple.
- Breast self-exam and mammography can help find breast cancer early when it is most treatable.
- the treatment of primary breast cancer usually consists of surgery, often followed by adjuvant therapy (radiotherapy, chemotherapy, hormonal treatment, etc.).
- Different types of treatment are available for patients with breast cancer. Most patients with breast cancer have surgery to remove the cancer from the breast, and several different surgical procedures exist for breast cancer removal. Other treatments include radiation therapy, a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing.
- Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.
- Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing.
- Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells, using for example monoclonal antibodies and tyrosine kinase inhibitors.
- the 2014 World Cancer Report from WHO (The World health organization) reports that breast cancer is the second most common cancer worldwide, accounting for just over 1 million new cases annually. It states that in 2000 (the last year for which global data exists) about 400,000 women died from breast cancer, representing 1.6 per cent of all female deaths. The proportion of breast cancer deaths was far higher in the rich countries (2 per cent of all female deaths) than in economically poor regions (0.5 per cent). Thus, breast cancer is strongly related to the Western lifestyle. As developing countries succeed in achieving lifestyles similar to Europe, North America, Australia, New Zealand and Japan, they will also encounter much higher cancer rates, particularly cancers of the breast. Recent data supports this prediction and show a 20% increase in breast cancer from 2008 to 2012.
- the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing desloratadine or loratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
- desloratadine or loratadine for use in treatment of breast cancer, wherein the treatment also comprises at least one immune check point modifier.
- desloratadine or loratadine for use in treating of preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
- desloratadine or loratadine for use in treating of preventing metastases resulting from at least one primary breast cancer tumour, wherein the treatment also comprises at least one immune check point modifier
- Fig- 1 is a graph showing the average change in body weight for the 6 different groups of mice in the study
- Fig- 2 is a graph showing the average change in tumor growth for the 6 different groups of mice in the study
- Fig- 3 are two graphs showing the average tumor growth for the 6 different groups of mice in the study.
- Fig- 4 are two graphs showing the average tumor size and weight for the 6 different groups of mice in the study at termination; different groups of mice in the study;
- Fig. 5 is a graph showing the total number of lung metastasis for the 6 different groups of mice in the study
- Fig. 6 is a graph showing the total number of small metastasis ( ⁇ 1.5 mm) for the 6 different groups of mice in the study;
- Fig. 7 is a graph showing the total number of large metastasis (>1.5 mm) for the 6 different groups of mice in the study;
- Fig. 8 is a graph summarizing the results for all metastasis for the 6 different groups of mice in the study.
- Fig. 9 is a graph summarizing the results for small metastasis ( ⁇ 1.5 mm) for the 6 different groups of mice in the study.
- Fig. 10 is a graph summarizing the results for large metastasis (>1.5 mm) for the 6 different groups of mice in the study.
- Hl receptor antihistamine for use in the treatment of breast cancer, the Hl receptor antihistamine being desloratadine or loratadine.
- the treatment of desloratadine or loratadine together may be used together with checkpoint therapy, preferably a PD-1 agonist.
- the breast cancer is selected from the group consisting of positive and negative ER (estrogen receptor), PR (progesterone receptor), her2 (human epidermal growth factor receptor 2) breast cancer molecular subtypes, and invasive breast carcinomas. Alternatively, it is selected from the group consisting of positive and negative ER invasive breast carcinomas.
- the treatment is typically continuous for at least 50 days, preferably at least 100 days and most preferably at least 1 year, most preferably 4 years.
- Antihistamines have received more and more attention as a potential group of drugs with anti-tumour effects.
- population based national registry data in Sweden from a time period when prescription of anti-histamines still was under patent protection for allergic or autoimmune conditions we first showed a survival benefit in breast cancer in mainly desloratadine users but also to a minor degree in loratadine and ebastine users (WO 2016/116438). Since these exciting results were based on database studies, more detailed studies are required to understand the function of how the anticancer effect is achived.
- the breast cancer is triple negative breast cancer.
- Desloratadine and loratadine are second-generation Hl -antihistamines, and desloratadine is a major metabolite of loratadine. As such, these share several similarities, therefore a similar effect is expected for both loratadine as for desloratadine.
- the second-generation Hl -antihistamine is desloratadine.
- desloratadine or loratadine for use in treatment of breast cancer wherein the dose is at least 25 mg per day, such as 25 to 100 mg per day, such as 25 to 50 mg per day, such as 25 mg per day.
- Desloratadine and loratadine is preferably administered on a daily basis to the subject being treated.
- Desloratadine and loratadie have well known pharmaceutical properties, such as absorption, bioavailability and half-life, and can as such be administered orally, for instance in tablet form, for easy use.
- Orally administered desloratadine has been shown to be well absorbed with maximum concentration achieved after approximately 3 hours and a half-life just over 24 hours. As such, oral administration once daily is possible.
- the prescribed dose is administered daily to the subject being treated. In one further embodiment, the administration is oral.
- tumour metastasis The effect on tumour metastasis is highly exciting and promising, since most terminal breast cancer patients have severe metastasis.
- the breast cancer to be treated is metastatic breast cancer.
- the treatment is to prevent metastasis originating from breast cancer.
- desloratadine or loratadine for use in use in treating or preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
- the treatment thus also comprises at least one immune check point inhibitor, such as immune check point inhibitor PD-1 (Programmed cell death protein 1) .
- immune check point inhibitor PD-1 Protein 1
- the PD-1 inhibitor is preferably administered following its prescribed method of administration.
- the PD-1 inhibitor was administered to the subject on weekly basis, being administered separately from the administered desloratadine and loratadine (which was administered on a daily basis).
- immune check point inhibitor may perform best when administered in combination, such as PD-1 inhibitors together with CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitors.
- immune check point inhibitors from PD-1, PD-L1 (programmed death-ligand 1) and CTLA-4 may be used, alone or in combination in the invention.
- the at least one immune check point inhibitor is selected from the group comprising of CTLA-4 inhibitors, PD-L1 inhibitors and PD-1 inhibitors, or a combination of two or more of these.
- CTLA-4 inhibitors examples include Ipilimumab or tremelimumab; Atezolizumab, Durvalumab or Avelumab; and Pembrolizumab, Nivolumab, Dostarlimab, Cemiplimab, Tislelizumab (BGB-A317) or InVivoMab clone RMP1-14 anti-PD-1 -antibody, respectively.
- the PD-1 inhibitors are selected from the group consisting of Pembrolizumab (Keytruda), Nivolumab (Opdivo), Dostarlimab (Jemperli), Cemiplimab (Libtayo), Tislelizumab (BGB-A317), and InVivoMab clone RMP1-14 anti-PD-1 -antibody;
- the PD-L1 inhibitors are selected from the group consisting of Atezolizumab (Tecentriq), Durvalumab (Imfinzi) or Avelumab (Bavencio);
- the CTLA-4 inhibitors are selected from the group consisting of Ipilimumab (Yervoy) and tremelimumab.
- the PD-1 inhibitors are selected from the group consisting of Pembrolizumab (Keytruda), nivolumab (Opdivo), and InVivoMab clone RMP1-14 anti-PD-1 -antibody;
- the PD-L1 inhibitors are selected from the group consisting of Atezolizumab and Durvalumab;
- the CTLA-4 inhibitors are selected from the group consisting of ipilumab.
- the PD-1 inhibitor is nivolumab
- the PD-L1 inhibitor is Durvalumab
- the CTLA-4 inhibitor is Ipilimumab.
- Humans with advanced or metastatic breast cancer is thus expected to benefit from high dose desloratadine or desloratadine, optionally in combination with a PD-1 inhibitor.
- the immune check point modifier is a PD-1 inhibitor.
- the immune check point modifier is a PD-1 inhibitor selected from the group consisting of Pembrolizumab (Keytruda), Nivolumab (Opdivo), Dostarlimab (Jemperli), Cemiplimab (Libtayo), Tislelizumab (BGB-A317), or InVivoMab clone RMP1-14 anti-PD-1 -antibody.
- the PD-1 agonist is an anti-PD-1 -antibody, such as InVivoMab clone RMP1-14.
- the dose of anti-PD-1- antibody is at least 25 mg weekly, such as at least 25 to 75 mg weekly, such as 50 mg weekly.
- Desloratadine is a complete H-l inverse antagonist unique by even blocking constitutive receptor activity and having a complete tissue distribution.
- immune check point modifiers such as CTLA-4, PD-L1 and PD-1.
- CTLA-4 a number of immune check point modifiers
- PD-L1 a number of immune check point modifiers
- the synergistic effect shown together with PD-1 inhibitors may point to an independent pathway for the hl receptor agonists.
- H-l blockade An independent effect from H-l blockade is also suggested by that it is not in humans a generalised effect on all tumour types but more on types with an immune profile.
- the data in the invention shows a synergistic effect between loratadine and desloratadine (desloratadine) intake and immune check point (PD-1) inhibition.
- Human and animal data suggest that a high dose (>25 mg per day) is better than a low dose (7 mg per day), that a continues treatment period is better than intermittent treatments and that a longer therapy such as 1 years is better than a shorter period, such as 30 days.
- the daily administration is continued for a period preferably more than 60 days, more preferably more than 1 year, even more preferably more than 4 years.
- Desloratadine being a nontoxic drug used by millions of individuals worldwide, provide a safe and cheap addition to the cancer therapy arsenal. Also, the synergy shown with immune check point blockade, provides another treatment. Due to its low risk and positive effects on metastasis, it is also ideal for prophylactic treatment for risk subjects, or subjects with an early primary tumor.
- peri-operational patients having their tumor removed would benefit from such treatment of the invention, to make sure remaining cells would not result in metastases. It could also be used simultaneously with other cancer treatments, such as with radiotherapy, chemotherapy and/or hormonal treatment.
- desloratadine or loratadine for use in the prophylactic treatment of metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
- the patient is perioperational.
- the patient further is treated with radiotherapy, chemotherapy and/or hormonal treatment.
- desloratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
- desloratadine for use in treating or preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
- Desloratadine or loratadine, or desloratadine or loratadine and a check point inhibitor may obviously also be used in method for treating such diseases and disorders as have been disclosed herein e.g. treatment of breast cancer or for use in treating or preventing metastases resulting from at least one primary breast cancer tumour.
- Such a method includes the step of administering an effective amount (at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day) of desloratadine or loratadine, or deloratadine and loratadine and a check point inhibitor, to a subject in need for such treatment.
- Desloratadine or loratadine, or desloratadine or loratadine and a check point inhibitor may also be used for the manufacture of a medicament for use in such treatment as disclosed herein, e.g. treatment of breast cancer or treating or preventing metastases resulting from at least one primary breast cancer tumour.
- one embodiment relates to a pharmaceutical composition, comprising desloratadine and/or loratadine and an excipient, for use in the treatment of breast cancer or treating or preventing metastases resulting from at least one primary breast cancer tumour.
- Doses are describes as HED (human ekvivalent dose) to the corresponding mice dose (mg/kg).
- the PD-1 agonist is an anti-PD-1 -antibody (InVivoMab clone RMP1-14), and dose was 50 mg HED administered day 10, 17 and 22.
- mice low dose desloratadine (HED) 7mg (1.5 mg/kg)) daily mice low dose desloratadine (HED) 7mg (1.5 mg/kg) daily
- mice high dose desloratadine (HED 25mg (5.0 mg/kg)) daily,
- mice a-PD-1 administered day 10, 17 and 22 i.p.
- Tumors were dissected and prepared for subsequent analyses.
- the lungs were insufflated with india-ink for metastatic analyses. Tumora were frozen and saved for possible future analyses.
- LM lung metastasis
- LM lung metastasis
- the reduuction is 1.7%/mg P ⁇ 0.001.
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Abstract
In the invention is provided desloratadine or loratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as 25 mg per day. Furthermore, the treatment may also comprises at least one immune check point modifier. Also provided is desloratadine or loratadine for use in treating of preventing metastases resulting from at least one primary breast cancer tumour.
Description
DESLORATADINE OR LORATADINE FOR USE IN THE TREATMENT OF BREAST CANCER
Field of the Invention
This invention pertains in general to the field of breast cancer treatment. Furthermore, the invention pertains to a breast cancer treatment that prevents or lessens lung cancer metastasis from breast cancer. More particularly the invention relates to a medicament for breast cancer treatment.
Background of the Invention
It is known that breast cancer is the most common cancer types for women, and affects one in eight women during their lives. Risk factors for breast cancer include, gender, age, genes, personal factors and other risks such as being overweight, using hormone replacement therapy (also called menopausal hormone therapy), taking birth control pills, drinking alcohol, not having children or having your first child after age 35 or having dense breasts.
Symptoms of breast cancer may include a lump in the breast, a change in size or shape of the breast or discharge from a nipple. Breast self-exam and mammography can help find breast cancer early when it is most treatable. The treatment of primary breast cancer usually consists of surgery, often followed by adjuvant therapy (radiotherapy, chemotherapy, hormonal treatment, etc.).
Different types of treatment are available for patients with breast cancer. Most patients with breast cancer have surgery to remove the cancer from the breast, and several different surgical procedures exist for breast cancer removal. Other treatments include radiation therapy, a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing. Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells, using for example monoclonal antibodies and tyrosine kinase inhibitors.
The 2014 World Cancer Report from WHO (The World health organization) reports that breast cancer is the second most common cancer worldwide, accounting for just over 1 million new cases annually. It states that in 2000 (the last year for which global data exists) about 400,000 women died from breast cancer, representing 1.6 per
cent of all female deaths. The proportion of breast cancer deaths was far higher in the rich countries (2 per cent of all female deaths) than in economically poor regions (0.5 per cent). Thus, breast cancer is strongly related to the Western lifestyle. As developing countries succeed in achieving lifestyles similar to Europe, North America, Australia, New Zealand and Japan, they will also encounter much higher cancer rates, particularly cancers of the breast. Recent data supports this prediction and show a 20% increase in breast cancer from 2008 to 2012.
Thus, there is a strong need for new types of treatment for breast cancer.
Summary of the Invention
Accordingly, the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing desloratadine or loratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
Furthermore, there is provided desloratadine or loratadine for use in treatment of breast cancer, wherein the treatment also comprises at least one immune check point modifier.
Also provided is desloratadine or loratadine for use in treating of preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
Furthermore, there is provided desloratadine or loratadine for use in treating of preventing metastases resulting from at least one primary breast cancer tumour, wherein the treatment also comprises at least one immune check point modifier
Brief Description of the Drawings
These and other aspects, features and advantages of which the invention is capable of will be apparent and elucidated from the following description of embodiments of the present invention, reference being made to the accompanying drawings, in which
Fig- 1 is a graph showing the average change in body weight for the 6 different groups of mice in the study;
Fig- 2 is a graph showing the average change in tumor growth for the 6 different groups of mice in the study;
Fig- 3 are two graphs showing the average tumor growth for the 6 different groups of mice in the study;
Fig- 4 are two graphs showing the average tumor size and weight for the 6 different groups of mice in the study at termination; different groups of mice in the study;
Fig. 5 is a graph showing the total number of lung metastasis for the 6 different groups of mice in the study;
Fig. 6 is a graph showing the total number of small metastasis (<1.5 mm) for the 6 different groups of mice in the study;
Fig. 7 is a graph showing the total number of large metastasis (>1.5 mm) for the 6 different groups of mice in the study;
Fig. 8 is a graph summarizing the results for all metastasis for the 6 different groups of mice in the study;
Fig. 9 is a graph summarizing the results for small metastasis (<1.5 mm) for the 6 different groups of mice in the study; and
Fig. 10 is a graph summarizing the results for large metastasis (>1.5 mm) for the 6 different groups of mice in the study.
Description of embodiments
It is an object of the present invention, considering the disadvantages mentioned above, to provide a treatment of a patient diagnosed with breast cancer. Also, to provide a treatment to hinder, treat or minimize lung metastasis resulting from a primary breast cancer tumour.
These and other objects, which will appear from the following description, have now been achieved by a Hl receptor antihistamine for use in the treatment of breast cancer, the Hl receptor antihistamine being desloratadine or loratadine. Also, the treatment of desloratadine or loratadine together may be used together with checkpoint therapy, preferably a PD-1 agonist.
The breast cancer is selected from the group consisting of positive and negative ER (estrogen receptor), PR (progesterone receptor), her2 (human epidermal growth factor receptor 2) breast cancer molecular subtypes, and invasive breast carcinomas. Alternatively, it is selected from the group consisting of positive and negative ER invasive breast carcinomas.
The treatment is typically continuous for at least 50 days, preferably at least 100 days and most preferably at least 1 year, most preferably 4 years.
Antihistamines have received more and more attention as a potential group of drugs with anti-tumour effects. Using population based national registry data in Sweden from a time period when prescription of anti-histamines still was under patent protection for allergic or autoimmune conditions we first showed a survival benefit in breast cancer in mainly desloratadine users but also to a minor degree in loratadine and ebastine users (WO 2016/116438). Since these exciting results were based on database studies, more detailed studies are required to understand the function of how the anticancer effect is achived.
In this study (cf. materials and method herein below), this effect has been probed in immuno competent mice, BALB/C 4T1, and the effect on tumor size and lung metastases were studied in mice untreated and in mice treated with different dose of desloratadine by itself or in combination with PD-1 antagonist (N=190). These breast cancer model mimics triple negative breast cancer in humans and carry the histamine receptor 1.
In one embodiment, the breast cancer is triple negative breast cancer.
Desloratadine and loratadine are second-generation Hl -antihistamines, and desloratadine is a major metabolite of loratadine. As such, these share several similarities, therefore a similar effect is expected for both loratadine as for desloratadine. In one embodiment, the second-generation Hl -antihistamine is desloratadine.
In the study of the invention, no significant differences in the weight or volume of the primary tumour was seen, although a small effect was shown for the loratadine (high dose, HED 25 mg) and PD-1 inhibitor group. The small differences in volume of the primary tumor is likely connected to that the mouse trials had to be ended on day 34. Also, several mice in the vehicle (control group) had to be removed from the study earlier than day 34 due to tumour size. However, surprisingly there was a significant lower number of lung metastases in mice treated with high dose desloradine HED 25 mg (5/mg/kg) daily compared with vehicle.
As such, in one embodiment, there is provided desloratadine or loratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 100 mg per day, such as 25 to 50 mg per day, such as 25 mg per day.
Desloratadine and loratadine is preferably administered on a daily basis to the subject being treated.
Desloratadine and loratadie have well known pharmaceutical properties, such as absorption, bioavailability and half-life, and can as such be administered orally, for instance in tablet form, for easy use.
Orally administered desloratadine has been shown to be well absorbed with maximum concentration achieved after approximately 3 hours and a half-life just over 24 hours. As such, oral administration once daily is possible.
In one embodiment, the prescribed dose is administered daily to the subject being treated. In one further embodiment, the administration is oral.
The effect on tumour metastasis is highly exciting and promising, since most terminal breast cancer patients have severe metastasis.
In one embodiment, the breast cancer to be treated is metastatic breast cancer.
In one embodiment, the treatment is to prevent metastasis originating from breast cancer.
In one embodiment there is provided desloratadine or loratadine for use in use in treating or preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
The effect on lung metastases of high dose desloratadine was similar to the effect when given in combination with immune check point inhibitor PD-1 (Programmed cell death protein 1). An especially low number of both small and large lung metastases was seen in mice that received treatment with high dose desloratadine and PD-1 in combination. It should be noted that PD-1 alone did not show significantly better results than the vehicle with regards to treating or preventing lung metastases.
In one embodiment, the treatment thus also comprises at least one immune check point inhibitor, such as immune check point inhibitor PD-1 (Programmed cell death protein 1) .
The PD-1 inhibitor is preferably administered following its prescribed method of administration. In this study, the PD-1 inhibitor was administered to the subject on weekly basis, being administered separately from the administered desloratadine and loratadine (which was administered on a daily basis).
Earlier animal models have shown that immune check point inhibitor may perform best when administered in combination, such as PD-1 inhibitors together with CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitors. As such, immune check point inhibitors from PD-1, PD-L1 (programmed death-ligand 1) and CTLA-4, may be used, alone or in combination in the invention.
In one embodiment, the at least one immune check point inhibitor is selected from the group comprising of CTLA-4 inhibitors, PD-L1 inhibitors and PD-1 inhibitors, or a combination of two or more of these. Examples of CTLA-4 inhibitors, PD-L1 inhibitors and PD-1 inhibitors are Ipilimumab or tremelimumab; Atezolizumab, Durvalumab or Avelumab; and Pembrolizumab, Nivolumab, Dostarlimab, Cemiplimab, Tislelizumab (BGB-A317) or InVivoMab clone RMP1-14 anti-PD-1 -antibody, respectively.
In one embodiment, the PD-1 inhibitors are selected from the group consisting of Pembrolizumab (Keytruda), Nivolumab (Opdivo), Dostarlimab (Jemperli), Cemiplimab (Libtayo), Tislelizumab (BGB-A317), and InVivoMab clone RMP1-14 anti-PD-1 -antibody; the PD-L1 inhibitors are selected from the group consisting of Atezolizumab (Tecentriq), Durvalumab (Imfinzi) or Avelumab (Bavencio); the CTLA-4 inhibitors are selected from the group consisting of Ipilimumab (Yervoy) and tremelimumab.
In one further embodiment, the PD-1 inhibitors are selected from the group consisting of Pembrolizumab (Keytruda), nivolumab (Opdivo), and InVivoMab clone RMP1-14 anti-PD-1 -antibody; the PD-L1 inhibitors are selected from the group consisting of Atezolizumab and Durvalumab; the CTLA-4 inhibitors are selected from the group consisting of ipilumab.
In one further embodiment, the PD-1 inhibitor is nivolumab, the PD-L1 inhibitor is Durvalumab, and the CTLA-4 inhibitor is Ipilimumab.
Low dose desloratadine, HED (human equivalent dose) 7mg (1.5 mg/kg), was alone or in combination with PD-1 inhibition not better than vehicle.
However, in this breast cancer model high dose desloratadine (HED 25 mg) by itself, or in combination with PD-1 inhibition, lowered the number of lung metastases compared with vechicle, low dose desloratadine (HED 7mg) or PD-1 inhibition alone.
Humans with advanced or metastatic breast cancer is thus expected to benefit from high dose desloratadine or desloratadine, optionally in combination with a PD-1 inhibitor.
In one embodiment, the immune check point modifier is a PD-1 inhibitor.
In one embodiment, the immune check point modifier is a PD-1 inhibitor selected from the group consisting of Pembrolizumab (Keytruda), Nivolumab (Opdivo), Dostarlimab (Jemperli), Cemiplimab (Libtayo), Tislelizumab (BGB-A317), or InVivoMab clone RMP1-14 anti-PD-1 -antibody.
In one embodiment, the PD-1 agonist is an anti-PD-1 -antibody, such as InVivoMab clone RMP1-14. In one further embodiment, the dose of anti-PD-1- antibody is at least 25 mg weekly, such as at least 25 to 75 mg weekly, such as 50 mg weekly.
In figures 8 to 10, it is clearly shown that both the primary tumours are both smaller and number of lung metastases are fewer in BALB/c mice given desloratadine and that this is dose dependent.
In this hormone receptor negative, immuno competent, orthotopically inoculated mice breast cancer model a synergy could also be seen between desloratadine and PD-1 therapy, while a minor effect could be seen with PD-1 alone.
Data suggest a stronger effect on metastatic disease than on the primary tumour. Especially large lung metastases were fewer. In this context a combination of PD-1 inhibition and a high desloratadine dose seemed especially favourable. The data further suggest that desloratadine at least partly work through an independent pathway from conventional immune check point therapy.
The breast tumous in BALB/c mice carry the H-l receptor. Desloratadine is a complete H-l inverse antagonist unique by even blocking constitutive receptor activity and having a complete tissue distribution. The effect seen by loratadine in human studies, being the mother substance of desloratadine, could at least partly be due to metabolisation of loratadine to desloratadine.
Likewise, a number of immune check point modifiers have become known such as CTLA-4, PD-L1 and PD-1. The synergistic effect shown together with PD-1 inhibitors may point to an independent pathway for the hl receptor agonists.
One concern in the human studies has been if the underlying disease/condition treated by antihistamine could be related to the effect. However, effects should then be seen for all the antihistamines and not only for desloratadine and loratadine, which have not been seen in the observational human studies. Further some tumour types are devoid of desloratadine effect. In the animals the effect is also seen in a strain (BALB/c 4T1) without allergy and autoimmunity.
An independent effect from H-l blockade is also suggested by that it is not in humans a generalised effect on all tumour types but more on types with an immune profile.
In summary, as are shown in figures 5 to 10, the data in the invention shows a synergistic effect between loratadine and desloratadine (desloratadine) intake and immune check point (PD-1) inhibition.
Human and animal data suggest that a high dose (>25 mg per day) is better than a low dose (7 mg per day), that a continues treatment period is better than intermittent treatments and that a longer therapy such as 1 years is better than a shorter period, such as 30 days.
Thus in one embodiment, the daily administration is continued for a period preferably more than 60 days, more preferably more than 1 year, even more preferably more than 4 years.
Desloratadine, being a nontoxic drug used by millions of individuals worldwide, provide a safe and cheap addition to the cancer therapy arsenal. Also, the synergy shown with immune check point blockade, provides another treatment. Due to its low risk and positive effects on metastasis, it is also ideal for prophylactic treatment for risk subjects, or subjects with an early primary tumor.
Also, peri-operational patients having their tumor removed would benefit from such treatment of the invention, to make sure remaining cells would not result in metastases. It could also be used simultaneously with other cancer treatments, such as with radiotherapy, chemotherapy and/or hormonal treatment.
Thus, in one embodiment is provided desloratadine or loratadine for use in the prophylactic treatment of metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
In one embodiment, the patient is perioperational.
In one embodiment, the patient further is treated with radiotherapy, chemotherapy and/or hormonal treatment.
In one embodiment, is provided desloratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
In one embodiment, in provided desloratadine for use in treating or preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
Desloratadine or loratadine, or desloratadine or loratadine and a check point inhibitor, may obviously also be used in method for treating such diseases and disorders as have been disclosed herein e.g. treatment of breast cancer or for use in treating or preventing metastases resulting from at least one primary breast cancer tumour. Such a method includes the step of administering an effective amount (at least 25 mg per day,
such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day) of desloratadine or loratadine, or deloratadine and loratadine and a check point inhibitor, to a subject in need for such treatment.
Evidently, Desloratadine or loratadine, or desloratadine or loratadine and a check point inhibitor, may also be used for the manufacture of a medicament for use in such treatment as disclosed herein, e.g. treatment of breast cancer or treating or preventing metastases resulting from at least one primary breast cancer tumour.
Thus, one embodiment relates to a pharmaceutical composition, comprising desloratadine and/or loratadine and an excipient, for use in the treatment of breast cancer or treating or preventing metastases resulting from at least one primary breast cancer tumour.
Material and Methods
The effects of desloratadine administration has been probed in immuno competent mice, BALB/C 4T1. The effect on tumor size and lung metastases were studied in mice untreated and in mice treated with different dose of desloratadine by itself or in combination with PD-1 antagonist (N=190). These breast cancer model mimics triple negative breast cancer in humans and carry the histamine receptor 1.
The study was undertaken in immuno competent mice, BALB/C and inoculated with 4T1 cells ortotopic 7x103 cells/mice in 50% matrigel.
Doses are describes as HED (human ekvivalent dose) to the corresponding mice dose (mg/kg). The PD-1 agonist is an anti-PD-1 -antibody (InVivoMab clone RMP1-14), and dose was 50 mg HED administered day 10, 17 and 22.
Six groups were formed;
1. 30 mice vehicle,
2. 30 mice low dose desloratadine (HED) 7mg (1.5 mg/kg)) daily,
3. 30 mice high dose desloratadine (HED 25mg (5.0 mg/kg)) daily,
4. 30 mice a-PD-1 (administered day 10, 17 and 22 i.p.),
5. 30 mice low dose desloratadine (HED 7mg (1.5 mg/kg)) daily, and a-PD- 1 (administered day 10, 17 and 22 i.p.),
6. 30 mice high dose desloratadine (HED 25mg (5.0 mg/kg)) daily and a- PD-1 (administered day 10, 17 and 22 i.p.),
At day 10 after breast tumour cells been inoculated, treatment with desloratadine begun. Measurement of tumour weight/size was undertaken every 3rd day. At the completion of the study at day 34 the number of lung metastases (total, small <1.5 mm and > 1.5mm) was measured.
Tumors were dissected and prepared for subsequent analyses. The lungs were insufflated with india-ink for metastatic analyses. Tumora were frozen and saved for possible future analyses.
Results
All the results are summarized in figures 1 to 10. As can be seen:
• A strong correlation exists between breast tumour size at termination and number of lung metastases.
• The size of the primary tumour at day 34 does not differ between the 6 groups.
• One complication in the study is that among 13 animals the growth was so rapid that the experiment needed to be terminated before day 34 (due to animal ethics) and 5 of these occurred in the vehicle group. In 4 other mice no primary tumour developed.
• Best results, highest significance, was seen for the combination desloratadine high dose+PD-1 for number of total lung metastases, number of large lung metastases > 3mm or small lung metastses <3 mm. (in the analyses adjustments were done for batch analysis and size of the primary tumour at termination).
• High dose desloratadine (25 mg HED) was better than low dose (7mg), p<0.09, and compared with vehicle ,p<0.11.
• Combining groups treated with high dose desloratadine (high dose desloratadine, high dose desloratadine+ PD-1) this was significantly better than vehicle. This is not seen when combining low dose desloratadine (low dose desloratadine, low dose desloratadine+PD-1)
• PD-1 was not significantly better than vehicle regarding lung metastases.
• High dose desloratadine+PD-1 is better than PD-1 with significantly fewer lung metastases.
The statistical analysis of the data shows that:
Primary tumor desloratadine effect
PD1- no significant difference for high dose vs. lowdose + placebo p=n.s.
120.3 95%CI (12.0 - 228.6) P=0.0298 P<0.029
PD1+ significant difference high dose vs. low donse + placebo p<0.047 Average value difference of 182.6 95%CI (1.25 - 182.6)
Total lungmetastasis number — desloratadine effect
PD1- Reduction of number of lung metastasis (LM) is on average
1.2%/mg (0.7 - 1.6%) P < 0.001 PO.0292
PD1+ Reduction of number of lung metastasis is
2.1%/mg PO.OOl
Total small lung metastasis
PD1- Reduction of number of lung metastasis (LM) is on average
1.3%/mg (0.8% - 1.8%), PO.OOl P=0.352
PD1+ The reduuction is 1.7%/mg P < 0.001.
Total large lung metastasis
PD1- Reduction of number of lung metastasis (LM) is on average 0%/mg (-1.6% - 0.3%), P=0.202
PD+ Reduction of number of lung metastasis
4.0%/mg P < 0.001.
Although the present invention has been described above with reference to (a) specific embodiment(s), it is not intended to be limited to the specific form set forth herein. Rather, the invention is limited only by the accompanying claims and, other embodiments than the specific above are equally possible within the scope of these appended claims, e.g. different ... than those described above.
In the claims, the term "comprises/comprising" does not exclude the presence of other elements or steps. Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented by e.g. a single unit or processor. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms "a", "an", “first”, “second” etc do not preclude a plurality. Reference signs in the claims are provided
merely as a clarifying example and shall not be construed as limiting the scope of the claims in any way.
Claims
1. Desloratadine or loratadine for use in treatment of breast cancer, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
2. Desloratadine or loratadine for use in treatment according to claim 1, wherein the breast cancer is metastatic breast cancer.
3. Desloratadine or loratadine for use in treatment according to claim 1 or 2, wherein the breast cancer is triple negative breast cancer.
4. Desloratadine or loratadine for use in treatment according to any one of claims 1 to 3, wherein the breast cancer is selected from the group consisting of positive and negative ER (estrogen receptor), PR (progesterone receptor), her2 (human epidermal growth factor receptor 2) breast cancer molecular subtypes, and invasive breast carcinomas.
5. Desloratadine or loratadine for use in treatment according to any one of claims 1 to 4, wherein the breast cancer is selected from the group consisting of positive and negative ER invasive breast carcinomas.
6. Desloratadine or loratadine for use in treatment according to any one of claims 1 to 5, wherein the treatment further comprises at least one immune check point inhibitor.
7. Desloratadine or loratadine for use in treatment according to claim 6, wherein the immune check point inhibitor is selected from the group consisting of CTLA-4 inhibitors, PD-L1 inhibitors, and PD-1 inhibitors, or a combination of these.
8. Desloratadine or loratadine for use in treatment according to claim 7, wherein the PD-1 inhibitors are selected from the group consisting of Pembrolizumab (Keytruda), Nivolumab (Opdivo), Dostarlimab (Jemperli), Cemiplimab (Libtayo), Tislelizumab (BGB-A317), and InVivoMab clone RMP1-14 anti-PD-1 -antibody; the PD-L1 inhibitors are selected from the group consisting of Atezolizumab (Tecentriq),
Durvalumab (Imfinzi) or Avelumab (Bavencio); the CTLA-4 inhibitors are selected from the group consisting of Ipilimumab (Yervoy) and tremelimumab.
9. Desloratadine or loratadine for use in treatment according to claim 7 or 8, wherein the immune check point inhibitor is a PD-1 inhibitor.
10. Desloratadine or loratadine for use in treatment according to claim 9, wherein the PD-1 inhibitor is an anti-PD-1 -antibody, such as InVivoMab clone RMP1- 14.
11. Desloratadine or loratadine for use in treatment according to claim 10, wherein the dose of anti-PD-1 -antibody is at least 25 mg weekly, such as at least 25 to 75 mg weekly, such as 50 mg weekly.
12. Desloratadine or loratadine for use in treatment according to any one of claims 1 to 11, wherein the desloratadine or loratadine is administered daily for preferably more than 60 days, more preferably more than 1 year, even more preferably more than 4 years.
13. Desloratadine or loratadine for use in treatment according to any of the preceding claims, wherein the treatment is administered to a breast cancer patient, wherein the patient is peri operational.
14. Desloratadine or loratadine for use in treatment according to any of the preceding claims, wherein the treatment is administered to a breast cancer patient, wherein the patient further is treated with radiotherapy, chemotherapy and/or hormonal treatment.
15. Desloratadine or loratadine for use in treating or preventing metastases resulting from at least one primary breast cancer tumour, wherein the dose is at least 25 mg per day, such as 25 to 200 mg per day, such as 25 to 50 mg per day, such as such as 25 mg per day.
16. Desloratadine or loratadine for use according to claim 15, wherein the metastasis are lung metastasis.
17. Desloratadine or loratadine for use in treatment according to claim 15 or 16, wherein the breast cancer is metastatic breast cancer.
18. Desloratadine or loratadine for use in treatment according to any one of claims 15 to 17, wherein the breast cancer is triple negative breast cancer.
19. Desloratadine or loratadine for use in treatment according to any one of claims 15 to 18, wherein the breast cancer is selected from the group consisting of positive and negative ER, PR, her2 breast cancer molecular subtypes, and invasive breast carcinomas.
20. Desloratadine or loratadine for use in treatment according to any one of claims 15 to 19, wherein the breast cancer is selected from the group consisting of positive and negative ER invasive breast carcinomas.
21. Desloratadine or loratadine for use in treatment according to any one of claims 15 to 20, wherein the treatment further comprises at least one immune check point inhibitor.
22. Desloratadine or loratadine for use in treatment according to claim 21, wherein the immune check point inhibitor is selected from the group consisting of CTLA-4 inhibitors, PD-L1 inhibitors and PD-1 inhibitors, or a combination of these.
23. Desloratadine or loratadine for use in treatment according to claim 22, wherein the PD-1 inhibitors are selected from the group consisting of Pembrolizumab (Keytruda), Nivolumab (Opdivo), Dostarlimab (Jemperli), Cemiplimab (Libtayo), Tislelizumab (BGB-A317), and InVivoMab clone RMP1-14 anti-PD-1 -antibody; the PD-L1 inhibitors are selected from the group consisting of Atezolizumab (Tecentriq), Durvalumab (Imfinzi) or Avelumab (Bavencio); the CTLA-4 inhibitors are selected from the group consisting of Ipilimumab (Yervoy) and tremelimumab.
24. Desloratadine or loratadine for use in treatment according to claim 22 or 23, wherein the immune check point inhibitor is a PD-1 inhibitor.
25. Desloratadine or loratadine for use in treatment according to claim 24, wherein the PD-1 inhibitor is an anti-PD-1 -antibody, such as InVivoMab clone RMP1- 14.
26. Desloratadine or loratadine for use in treatment according to claim 25, wherein the dose of anti-PD-1 -antibody is at least 25 mg weekly, such as at least 25 to 75 mg weekly, such as 50 mg weekly.
27. Desloratadine or loratadine for use in treatment according to any one of claims 15 to 26, wherein the desloratadine or loratadine is administered daily for preferably more than 60 days, more preferably more than 1 year, even more preferably more than 4 years.
28. The use according to any one of claims 15 to 27, wherein the treatment is administered to a breast cancer patient, wherein the patient is peri operational.
29. The use according to any one of claims 16 to 28, wherein the treatment is administered to a breast cancer patient, wherein the patient further is treated with radiotherapy, chemotherapy and/or hormonal treatment.
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| WO2016116438A1 (en) | 2015-01-19 | 2016-07-28 | Partners För Utvecklingsinvesteringar Inom Life Sciences, P.U.L.S. Ab | Antihistamine for use in treatment of breast cancer |
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2021
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016116438A1 (en) | 2015-01-19 | 2016-07-28 | Partners För Utvecklingsinvesteringar Inom Life Sciences, P.U.L.S. Ab | Antihistamine for use in treatment of breast cancer |
Non-Patent Citations (2)
| Title |
|---|
| FRITZ I ET AL: "Desloratadine and loratadine stand out among common H 1 -antihistamines for association with improved breast cancer survival - Supplemental material", ACTA ONCOLOGICA, 27 May 2020 (2020-05-27), XP055864238, Retrieved from the Internet <URL:https://www.tandfonline.com/doi/suppl/10.1080/0284186X.2020.1769185?scroll=top> [retrieved on 20211122] * |
| FRITZ ILDIKÓ ET AL: "Desloratadine and loratadine stand out among common H 1 -antihistamines for association with improved breast cancer survival", ACTA ONCOLOGICA., vol. 59, no. 9, 27 May 2020 (2020-05-27), GB, pages 1103 - 1109, XP055864229, ISSN: 0284-186X, DOI: 10.1080/0284186X.2020.1769185 * |
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