Intermittent dosing of mdm2 inhibitor

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...

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Benefits of technology

[0007]It has been unexpectedly discovered that an advantageous dosing regimen for a Mdm2 inhibitor (hereinafter “Mdm2i”) can be designed by understanding the biology of the drug target and how the Mdm2i concentration can alter signaling of the downstream pathway to affect anti-tumor efficacy and tolerability. Surprisingly, it was found that if a sufficiently potent Mdm2i or, in alternative, a sufficiently high dose of a Mdm2i is used, it can cause antineoplastic effect by triggering much longer lasting antiproliferative mechanism in cells. When a cancer cell is exposed to sufficiently high concentration of the respective Mdm2i for as short as 8 hours (and proportionally longer if a lower concentration is used), Mdm2i causes p21 and Puma mRNA expression to spike within the next 48 to 72 hours, leading to significant induction of caspase 3 / 7 activity and thus to substantial apoptosis. In animals that have had cancer cells implanted subcutaneously the same effect after treating the animal with a sufficiently high single dose was observed. This led to substantial tumor shrinkage. None of this was detected when the Mdm2i exposure was below a certain threshold below which this second modality of Mdm2i was not activated. The knowledge of the second modality of Mdm2i can help plan clinical trials in a way to reduce side effects due to an on-target effect of the drug.

[0008]Interestingly, it was observed that a long lasting effect can be sustained for several weeks after a single dose, which eliminates the need for daily treatment and allows administering the drug intermittently. During the breaks with no administration of a drug an organism can recover from potential on-target effects or side effects; particularly numbers of white blood cells (WBC), neutrophils and platelets can recover. Administering the Mdm2i at doses that trigger the long lasting effect causes the Mdm2i to be at least as effective as when dosed daily at lower doses, and can be better tolerated. Less frequent dosing can also lead to better patient friendliness, patient compliance, and particularly where the drug is administered intravenously, can have significant patient benefits. For example, the local injection site irritations can properly heal before the next dose is due.

[0009]The intermittent dosing of an Mdm2i with a sustained effect can be combined with a dosing regimen comprising a daily administration of a lower dose compared to the dose used to achieve a sustained effect. The combination of intermittent dosing of a first dose and daily dosing of a second dose yields synergistic effect in terms of the compound efficacy, which is observed for example as a tumor shrinkage or tumor regression. In addition, due to better tolerability of Mdm2i when administered intermittently, the drug can be used in combination with other antineoplastic agents. The combination of a Mdm2i and another antineoplastic agent can exploit improved tolerability of the Mdm2i when it is dosed intermittently, while increasing the overall efficacy of the combination therapy with a second antineoplastic agent.

[0010]Specifically, the present disclosure provides the following aspects, advantageous features and specific embodiments, respectively alone or in combination, as listed in the following items:

Problems solved by technology

This led to substantial tumor shrinkage.

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