Intermittent dosing of mdm2 inhibitor

a technology of mdm2 inhibitor and inhibitor, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, organic active ingredients, etc., can solve the problems of substantial tumor shrinkage, achieve high synergistic effect, improve efficacy, and increase tolerability

Inactive Publication Date: 2017-07-13
NOVARTIS AG
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  • Abstract
  • Description
  • Claims
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Benefits of technology

[0154]Experiments were done to evaluate the response of a high dose and a low dose. Animals were treated with low dose of 5 mg/kg p.o. or a high dose of 27 mg/kg p.o. or 20 mg/kg i.v. Low dose of Mdm2i does not trigger the same biochemical effect as does the high dose (FIG. 16).
[0155]The experiments were repeated on SJSA-1 tumour bearing rats with combining two dosing schedules of compound A, one intermittent (15 mg/kg once) and the daily dosing (1.5 mg/kg). We show on FIG. 17 that combining the two dosing regimens has a highly synergistic effect. This is a schematic presentation of multiple experiments. Further clear synergism can be seen also on FIGS. 1...

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  • Intermittent dosing of mdm2 inhibitor
  • Intermittent dosing of mdm2 inhibitor
  • Intermittent dosing of mdm2 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Pharmacokinetics (PK) of Compound A after Single i.v. Injection at 20 mg / kg

[0148]FIG. 1 shows Compound A concentration in plasma, tumor and liver over 144 hours after one single i.v. injection. The Tmax for the compound was 5 min in plasma and liver and 1 h in tumor. Compound A had a two times higher exposure in tumor (AUC0-144h dn=16.5 h.nmol / g) compared to plasma (AUC0-144h dn=8.1 h.μM). FIG. 2 shows the Compound A concentration in tumor and the pharmacodynamics (PD) response in tumor. Puma and p21 had a very similar mRNA induction reaching an expression max of 180 and 200-fold 24 h post treatment, respectively.

example 2

PK, PD, Efficacy and Tolerability of Compound A (i.v., once) on SJSA-1 Tumor-Bearing Rat

[0149]FIGS. 3 and 4, respectively show the tumor growth and the change in body weight of nude rats over 42 days. The single i.v. treatment with compound A at 20 mg / kg (the higher dose) induced 92% tumor regression 14 days post treatment. One rat had to be sacrificed on day 9 post treatment because of excessive body weight (BW) loss. In spite of a slight decrease in BW 3 days post treatment for all others rats, they recovered quickly and gained BW during the entire experiment. Only 2 of 11 tumors had an incomplete response and regrew (FIG. 5). These 2 animals were retreated i.v. at 15 mg / kg and the tumors were still sensitive. However, tumor regression was attenuated which could be due to the larger tumor size. After the first treatment, p21 and Puma mRNA expression in tumor reached a more than 50-fold increase in mRNA expression. Mdm2 had a much lower mRNA induction (Emax=10-fold). On day 59 post...

example 3

PK, PD, Efficacy and Tolerability of Compound A (i.v., q3w) on SJSA-1 Tumor-Bearing Rat

[0150]FIG. 8 shows the tumor growth and the change in body weight of nude rats over 42 days. Three weeks post first treatment at 20 mg / kg, compound A induced 6% tumor regression on average. However, individual data show that 3 rats had complete response (100% regression), 2 had partial response (more than 50% regression), 1 had stable disease and 1 had progressive disease in spite of an early 80% regression 1 week post treatment. After the second treatment, Compound A induced 100% tumor regression but only 2 / 7 animals survived the 2 full cycles. Indeed, 5 rats had to be sacrificed after the second treatment because of excessive BW loss: the first one 10 days post second treatment and the four others 8 days later. FIG. 9 shows the white blood cells (WBC), neutrophils and platelets count over the 42 days of experiment. Compound A induced a dramatic decrease in WBCs, neutrophils and platelets after t...

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Abstract

The present disclosure relates to mdm2 inhibitors for use in specific dosing schedules. It was found that if sufficiently potent or, in alternative, sufficiently high dose of a Mdm2 inhibitor is used, it can cause antineoplastic effect by triggering much longer lasting antiproliferative mechanism in cells. The long lasting effect can sustain for several weeks after a single dose, which eliminates the need for daily treatment and allows administering the Mdm2i intermittently. A treatment with the intermittent dosing schedule of a Mdm2 inhibitor can be combined with a daily treatment of the Mdm2i or with another pharmaceutically acceptable ingredient.

Description

FIELD OF THE DISCLOSURE[0001]The present disclosure relates to mdm2 inhibitors for use in specific dosing schedules.BACKGROUND OF THE DISCLOSURE[0002]The protein p53 is a transcription factor that controls the expression of a multitude of target genes involved in DNA damage repair, apoptosis and cell cycle arrest, which are all important phenomena counteracting the malignant growth of tumors. p53 is thus critical for maintaining genetic stability and preventing tumor development. The TP53 gene is one of the most frequently mutated genes in human cancers. It is reported that approximately half of all cancers have inactivated p53, caused by direct mutation. In cancers in which the p53 gene is not mutated, functional inactivation at the protein level has been demonstrated. One of the mechanisms of p53 inactivation described is through its interaction with human homolog of MDM2 (Mouse double minute 2). Mdm2 is therefore an important negative regulator of the p53 tumor suppressor. Mdm2 p...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K45/06A61K9/00
CPCA61K31/506A61K45/06A61K9/0019A61K31/402A61K31/404A61K31/4178A61K31/4418A61K31/4439A61K31/47A61K31/472A61K31/496A61P35/00A61P35/02A61P43/00A61K31/4725A61K31/40
Inventor FERRETTI, STEPHANEJEAY, SEBASTIEN
Owner NOVARTIS AG
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