Formulations of 6-(2-hydroxy-methylpropoxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
Inventors
Reynolds, Mark • Eary, Charles Todd
Assignees
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Publication Number
US-12102621-B2
Publication Date
2024-10-01
Expiration Date
Abstract
6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition (including solid formulations or liquid formulations) thereof and the use thereof for treating diseases and disorders which can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors, and gastrointestinal disorders such as IBS are disclosed.
Core Innovation
The invention relates to a liquid formulation comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the compound of Formula (I), or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof. The formulation further comprises an aqueous compounding agent comprising a glycol, an oil, an alcohol, a flavoring agent, a preservative, a stabilizer, a coloring agent, or a combination thereof. The disclosure also includes dependent formulation refinements specifying example aqueous compounding agents, a sweetener component, concentration, pH, and an aqueous sweetener to aqueous compounding agent ratio.
The disclosure relates to Formula (I) compounds as RET inhibitors and to their use in RET-associated cancer contexts. It describes treatment approaches in which cancer is determined to be RET-associated and a therapeutically effective amount of the liquid formulation is administered, including use in pediatric patients and in patients identified as having dysphagia. The description also references RET inhibitor resistance mutations, RET fusion proteins, RET gene dysregulation, and RET-associated cancer types.
The disclosure further describes solid-state and formulation characterization for the Formula (I) compound, including polymorph Forms 1, 2, 7, and 8, solid-state stability characterization, and analysis using XRPD, TGA, DSC, DVS, PLM, vapor sorption, and 1H NMR. It also references RET kinase inhibition, RET enzyme assay results, and a RET cell assay based on Kif5b-RET fusion in HEK-293.
Claims Coverage
The consolidated claim coverage includes three independent claim themes: a liquid formulation claim and two method-of-treatment claims. Across these claims, the inventive features center on a specific Formula (I) liquid formulation with an aqueous compounding agent and on conditional treatment of RET-associated cancer, including one claim further limited to patients having dysphagia.
Liquid formulation with aqueous compounding agent
A liquid formulation comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, the compound of Formula (I), or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof, wherein the formulation further comprises an aqueous compounding agent comprising a glycol, an oil, an alcohol, a flavoring agent, a preservative, a stabilizer, a coloring agent, or a combination thereof.
Treating RET-associated cancer with the liquid formulation
A method of treating cancer in a patient in need thereof comprising determining if the cancer is a RET-associated cancer and, if the cancer is determined to be a RET-associated cancer, administering to the patient a therapeutically effective amount of a liquid formulation comprising the compound of Formula (I), or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof.
Treating dysphagia patients with RET-associated cancer using the liquid formulation
A method of treating cancer in a patient in need thereof comprising identifying a patient in need thereof having dysphagia, determining if the cancer is a RET-associated cancer, and if the cancer is determined to be a RET-associated cancer, administering to the patient a therapeutically effective amount of a liquid formulation comprising the compound of Formula (I), or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof.
Overall, the claims protect a liquid formulation containing the Formula (I) RET inhibitor compound, together with an aqueous compounding agent, and conditional treatment methods in which administration follows determination that the cancer is RET-associated, with one method additionally limited to patients having dysphagia.
Stated Advantages
Nanomolar potency and selectivity as a RET inhibitor.
Activity against RET activating and inhibitor-resistance mutations.
Activity against RET fusions including KIF5B-RET.
Documented Applications
Liquid formulation use for delivering the Formula (I) compound, including pharmaceutically acceptable salt, amorphous form, or polymorph form thereof.
Treating RET-associated cancers by determining whether the cancer is RET-associated and administering a therapeutically effective amount of the liquid formulation containing the Formula (I) compound, including acceptable salt, amorphous form, or polymorph form thereof.
Treating pediatric patients with RET-associated cancers using the liquid formulation containing the Formula (I) compound.
Treating cancer in patients with dysphagia by identifying dysphagia, determining whether the cancer is RET-associated, and administering the liquid formulation containing the Formula (I) compound.
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