CN112439069A

CN112439069A - Application of VEGFR inhibitor in preparation of medicine for treating graft-versus-host disease

Info

Publication number: CN112439069A
Application number: CN202010874520.0A
Authority: CN
Inventors: 宋献民; 邹建军; 李华军
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2019-08-28
Filing date: 2020-08-27
Publication date: 2021-03-05

Abstract

The present disclosure relates to the use of a VEGFR inhibitor for the preparation of a medicament for the treatment of graft versus host disease. In particular, the Graft Versus Host Disease (GVHD) includes acute anti-host disease (aGVHD) and chronic anti-host disease (cGVHD), and the VEGFR inhibitor is selected from apatinib or a pharmaceutically acceptable salt thereof.

Description

Application of VEGFR inhibitor in preparation of medicine for treating graft-versus-host disease

Technical Field

The disclosure relates to use of a VEGFR inhibitor in the preparation of a medicament for treating an anti-host disease.

Background

Graft Versus Host Disease (GVHD) is generally classified by time of occurrence and clinical presentation into acute graft versus host disease (aGVHD) and chronic graft versus host disease (cGVHD). At present, first-line therapeutic agents for acute anti-host disease (aGVHD) are immunosuppressants, such as prednisone, methylprednisolone, dexamethasone, beclomethasone, budesonide and the like,recently, Ruxolitinib (

JAK1/2 inhibitor) is approved for the treatment of steroid refractory acute GVHD in adult and pediatric patients 12 years of age and older. Prednisone is the standard first-line therapy for chronic GVHD. For patients who do not respond to prednisone or other steroid therapy, the U.S. Food and Drug Administration (FDA) approves the drug ibrutinib

Second line treatment of adult chronic GVHD patients after failure as one or more other treatments.

Journal literature (Blood 2017129: 1865-1875) reports that acute graft versus host disease (aGVHD) is associated with lymphangiogenesis in the mouse allo-HSCT model and in intestinal biopsies of patients. Inhibition of aGVHD-associated lymphangiogenesis by monoclonal antibodies directed against vascular endothelial growth factor receptor 3(VEGFR-3) improved aGVHD and improved survival in murine models.

Apatinib is the first oral anti-angiogenesis drug for late gastric cancer in the world, has high selectivity on VEGFR-2, and has strong anti-angiogenesis effect. In a multicenter randomized double-blind placebo-controlled phase iii trial on patients with metastatic gastroesophageal junction cancer treated second line of apatinib, the results showed that apatinib single drug extended median overall survival by 1.8 months, median progression-free survival by 0.8 months, and controlled adverse events compared to placebo. The structural formula of apatinib is shown as follows:

disclosure of Invention

The present disclosure (The Discloissue) provides use of a VEGFR inhibitor selected from The group consisting of PAN-90806, Foretinib, Tafitinib (Tafetinib), Cornitinib (Kanitinib), Apatinib (Apatinib), Tanibirumab, Anlotinib (Anlotitinib), Delitinib (Lucitinib), Vatalaniib, Cediranib (Cediraniib), Sevoroniib (Chiaunib), Duivitinib (Dovitinib), Dunnafenib (Donafenib), Sinivatinib, Teratinib (Telatinib), L-21649, TAS-115, Cabozantinib (Cabozantinib), Thielafenib (Thiofenib), furacitinib (Teninib), Britisib (Britisib), Vernib (Vernib), Verninib (Verninib), Vernib (Verninib (Vernib), Verninib (Verninib), Vernib), Verninib (Vernib), Verninib (e (Verninib), Vernib), Verninib (Takaranibarbutinib (e), Verninib), Vernib), Verninib (e (E-115), HLX-06, Altiratinib, Ningetinib (Nigertinib), Sunitinib (Sunitinib), AL-8326, Rebastinib or pharmaceutically acceptable salts thereof, preferably apatinib or pharmaceutically acceptable salts thereof.

In some alternative embodiments, the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, preferably mesylate.

In some embodiments, the graft-versus-host disease is acute graft-versus-host disease.

In other embodiments, the graft-versus-host disease is a chronic graft-versus-host disease selected from, but not limited to, non-scleroderma, multi-organ, bronchiolitis obliterans syndrome.

Further, the patient in the present disclosure has been subjected to a cell transplantation, preferably a allogeneic bone marrow or hematopoietic stem cell transplantation.

In some embodiments, the VEGFR inhibitor is administered in combination with allogeneic bone marrow or hematopoietic stem cell transplantation.

In some embodiments, the VEGFR inhibitor is administered to a mammal at a dose of 0.1-10.0 mg/kg, and may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.6mg/kg, 4mg/kg, 4.5 mg/kg, 0mg/kg, 0.6mg/kg, 4mg/kg, 4.6mg/kg, 4mg/kg, 0, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg or any value therebetween.

In some embodiments, the VEGFR inhibitor is administered in a mammalian human at a dose of 1-850mg, and may be 1.0mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, 2.0mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 9.0mg, 9.45 mg, 20mg, 100mg, 15mg, 100mg, 25mg, 6mg, 6.6mg, 6mg, 6.6.8.8 mg, 6.0mg, 6mg, 9.0mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 455mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 500mg, 505mg, 510mg, 575mg, 520mg, 565mg, 530mg, 570mg, 530mg, 150mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 805mg, 810mg, 815mg, 820mg, 825mg, 830mg, 835mg, 840mg, 845mg, 850mg, or any value between any two values, preferably 12mg, 100mg, 150mg, 200mg, 250mg, 375mg, 500mg, or 850 mg.

Further, the VEGFR inhibitor in the uses of the present disclosure is administered in combination with one or more additional therapeutic agents.

In some embodiments, the additional therapeutic agent is an anti-GVHD therapeutic agent.

In some embodiments, the anti-GVHD therapeutic agent is an immunosuppressive agent (drug).

In some embodiments, the immunosuppressive agent (drug) comprises cyclosporine, tacrolimus (tacrolimus), methotrexate (methotrexate), mycophenolate mofetil, a corticosteroid, Azathioprine (ATG), or Antithymotryocyclin (ATG).

In some embodiments, the immunosuppressive agent (drug) is a monoclonal antibody, e.g., anti-CD 3, anti-CD 5, and anti-IL-2 antibodies.

In some embodiments, the immunosuppressive agent (drug) is mycophenolate mofetil, alemtuzumab, antithymocyte globulin (ATG), Sirolimus (Sirolimus), tacrolimus, thalidomide, Daclizumab (Daclizumab), Infliximab (Infliximab), or Clofazimine (Clofazimine) for the treatment of chronic GVHD.

In some embodiments, the additional therapeutic agent is a dinenikin interleukin (denileukin diftotox), defibrotide (defibrotide), budesonide (budesonide), beclomethasone dipropionate (beclomethasone dipionate), or pentostatin.

In some embodiments, the additional therapeutic agent is a Topically Active Corticosteroid (TAC).

In some embodiments, the TAC is beclomethasone dipropionate (diproprionate), budesonide, beclomethasone-17-monopropionate, betamethasone (betamethasone), clobetamethasone propionate (clobetamethasone), dexamethasone (dexamethasone), diflorodiazone diacetate (diflurasone diacetate), flunisolide (flunisolide), fluocinolone acetonide (fluocinonide), fluocinolone acetonide (flurandrenolide), fluticasone propionate (fluticasone propionate), halobetasol propionate (halobetasol propionate), halcinoside, mometasone furoate (mometasone furoate), triamcinolone acetonide (triamcinolone acetonide), or a combination thereof.

In some embodiments, the additional therapeutic agent is an antifungal agent. In some embodiments, the additional therapeutic agent is nystatin, clotrimazole, amphotericin, fluconazole, or a combination thereof.

In some embodiments, the additional therapeutic agent is a pro-salivation agent. In some embodiments, the additional therapeutic agent is cevimeline (pivameline), pilocarpine (pilocarpine), bethanechol, or a combination thereof.

In some embodiments, the additional therapeutic agent is a local anesthetic. In some embodiments, the additional therapeutic agent is lidocaine (lidocaine), dyclonine (dyclonine), diphenhydramine (diphenhydramine), doxepin (doxepin), or a combination thereof.

Further, the VEGFR inhibitor has a synergistic effect in combination with another therapeutic agent. Can effectively reduce the single administration dosage of VEGFR inhibitors such as apatinib or pharmaceutically acceptable salts thereof, and reduce adverse drug reactions.

In another aspect, the VEGFR inhibitor, such as apatinib, for use in the present disclosure is administered once a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in three days, once in one day per week, four days, once in one day per week, and five days, once in one day per week.

In some embodiments, the VEGFR inhibitor apatinib, or a pharmaceutically acceptable salt thereof, is administered to the mammal at a dose of 250-850mg at a dosing frequency of once a day.

The present disclosure also provides a pharmaceutical combination for treating graft versus host disease comprising a therapeutically effective amount of a VEGFR inhibitor. Further, the pharmaceutical combination further comprises an additional therapeutic agent.

Unless otherwise explained, terms in this disclosure have the following meanings:

the present disclosure with respect to "combination" or "combination" is a mode of administration, meaning that at least one dose of a VEGFR inhibitor, such as apatinib or a pharmaceutically acceptable salt thereof, and at least one dose of an additional therapeutic agent, both of which exhibit a pharmacological effect, are administered over a period of time. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The VEGFR inhibitor, such as apatinib, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent may be administered simultaneously or sequentially. Such terms include treatments wherein the VEGFR inhibitor, such as apatinib, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered by the same route of administration or different routes of administration. The mode of administration of the combinations described herein is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.

An "effective amount" or "therapeutically effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

Progression Free Survival (PFS): from random start to the date of first recording of objective tumor progression or to the time of death due to any cause, whichever occurred first.

Overall Survival (OS) refers to the period from random to death due to any cause. Subjects who survived the last visit had OS scored as data loss at the time of the last visit. Subjects who were missed their OS were data loss as the last confirmed survival time before the missed visit. The OS of data erasure is defined as the time from random grouping to erasure.

Responses were evaluated by NIH conformance criteria for GVHD ratings.

A Complete Response (CR) will be defined as a complete regression of symptoms attributable to GVHD.

Partial Response (PR) will be defined as the presence of an objective response in 1 affected organ, with no evidence of progression elsewhere and without requiring additional systemic therapy.

The length of follow-up will be 24 months and the estimated recruitment period will be 2 years.

Drawings

FIG. 1: inhibition of Whole splenocyte proliferation by apatinib

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Example 1:

cell experiment 1: taking the spleen of a normal mouse (C57BL/6), separating to obtain a mononuclear cell suspension, adding apatinib mesylate for co-culture after PMA (phorbol ester) + Ionomycin (Ionomycin) + IL-2 stimulation, and verifying the effect on whole splenocytes (more than 90 percent of the cells are immune cells);

cell experiment 2: the single cell suspension separated from the mouse spleen is separated to obtain CD4+ T cells and CD8+ T cells by using sorting magnetic beads, and the single cells are separately cultured in vitro, and the proliferation of the T cells is stimulated by using CD3/CD28 magnetic beads. Subsequently, apatinib mesylate is added into the CD4+ T cells and the CD8+ T cells respectively for co-culture, and the effect on the CD4+ T cells and the CD8+ T cells is verified.

Cell density: 1 x 10^6/ml

Apatinib mesylate concentration gradient range: 1-100 mu M

Culturing time: 72h

And (4) conclusion: the result of the cell experiment 1 shows that the apatinib mesylate has obvious effect of inhibiting proliferation of whole splenocytes (more than 90 percent of the splenocytes are immune cells), the curve of the cell inhibition rate and the drug concentration is shown in figure 1, and the 60 mu M cell inhibition rate is 0.4. Cell experiment 2 further demonstrated its feasibility as a therapeutic agent for GVHD.

EXAMPLE 2 Studies of Chronic GVHD clinical Studies

Grouping standard:

1. corticosteroid-resistant or corticosteroid-refractory classic or overlapping chronic GVHD (equivalent to at least 0.5 mg/kg/day or 1 mg/kg/every 2 days prednisone for at least 1 month of treatment). Allows organ-specific local therapy;

2. history of allogeneic stem cell transplantation for hematologic malignancies;

the administration method comprises the following steps:

scheme 1: compound a, apatinib mesylate, 500mg, administered orally on an empty stomach, once daily, can be prepared according to the method in patent application WO2010031266a 1;

scheme 2: compound a, apatinib mesylate, 375mg, was administered orally on an empty stomach once daily and was prepared according to the method in patent application WO2010031266a 1.

Claims

1. Use of a VEGFR inhibitor selected from PAN-90806, Foretinib, tamifatinib, canertinib, apatinib, Tanibirumab, antrotenib, dritinib, Vatalanib, cediranib, cissunitinib, seolotinib, doritinib, doraninib, sitavatinib, teratinib, taratinib, L-21649, TAS-115, cabozantinib, tiazafenib, furoquintinib, brionib, solitinib, ramucirumumab, glelatinib, nidab, priotinib, axitinib, EDP317, sorafenib, metetinib, Tivozanib, Regorafenib, migovanib (Regorafenib), misstaurin, Pazopanib (pazotinib), hlratinib 06, alsitinib, alitatinib 8326, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating graft-versus host disease.

2. Use according to claim 1, wherein the graft-versus-host disease is chronic graft-versus-host disease, preferably non-scleroderma, multi-organ, bronchiolitis obliterans syndrome.

3. The use of claim 1, wherein the graft-versus-host disease is acute graft-versus-host disease.

4. Use according to any one of claims 1 to 3, wherein the patient has received a cell transplant, preferably an allogeneic bone marrow or hematopoietic stem cell transplant.

5. The use of claim 4, wherein the VEGFR inhibitor is administered in conjunction with allogeneic bone marrow or hematopoietic stem cell transplantation.

6. The use of any of claims 1-5, wherein the VEGFR inhibitor is administered in a dose selected from the group consisting of 1-850mg, preferably 12mg, 20mg, 100mg, 150mg, 200mg, 250mg, 375mg, 500mg, or 850mg in a mammalian human.

7. The use of any of claims 1-6, wherein the VEGFR inhibitor is administered in combination with one or more additional therapeutic agents.

8. The use of claim 7, wherein the additional therapeutic agent is selected from a corticosteroid, cyclosporin, mycophenolate mofetil, or a combination thereof.

9. The use according to claim 1, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate and phosphate, preferably mesylate.

10. A pharmaceutical combination for treating graft versus host disease comprising a therapeutically effective amount of a VEGFR inhibitor.