Methods of treating retroviral infections and related dosage regimes
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9956239-B2
Publication Date
2018-05-01
Expiration Date
Abstract
The present invention relates to compounds and methods for treating retroviral infections and/or Hepatitis B viral infections. Some compounds of the invention are described by Formula I:or a stereoisomer, a diastereomer, an enantiomer or racemate thereof.
Core Innovation
The invention relates to treating or preventing retroviral infections and Hepatitis B viral infections by administering phosphonate ester tenofovir prodrug compounds of Formula I, including stereochemical variants and pharmaceutically acceptable salts. The disclosed compounds include CMX157 and hexadecyloxypropyl tenofovir (HDP-TFV), together with defined salt forms where M+ comprises cations such as K+, Na+, Li+, Ca2+, Mg2+, and nitrogen-containing cations of ammonium type.
The problem addressed is the need for antiviral treatment of retroviral infections and Hepatitis B viral infections with dosing regimens that support antiviral potency and intracellular persistence. The disclosure emphasizes that intracellular tenofovir-diphosphate (TFV-PP) levels and long intracellular half-life support lower dosage and infrequent dosing, and that activity is maintained in relevant settings including NRTI-resistant HIV isolates.
The method provides pharmaceutical compositions suitable for administration, including compositions for oral forms such as tablets and capsules and for injectable or topical formulations, with dosing administered daily or weekly in an amount of about 25 mg to about 2000 mg. The disclosure also describes antiviral activity and support from nonclinical and clinical-stage materials, including potency measures, intracellular TFV-PP persistence, and in vitro transport studies addressing OAT1 and OAT3 substrate potential relevance.
Claims Coverage
The document contains one independent claim directed to a method of treating a retroviral infection by administering a therapeutically effective amount of a compound of a specified structure or a pharmaceutically acceptable salt, with daily or weekly dosing in a defined mg range. Dependent claims refine the dosing frequency and dosage amount, narrow the target infection to HIV, and add combination therapy with additional antiviral agents.
Treating retroviral infection with Formula I phosphonate ester tenofovir prodrug
A method of treating a retroviral infection in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the structure or a pharmaceutically acceptable salt thereof, where the compound or pharmaceutically acceptable salt is administered daily or weekly in an amount of about 25 mg to about 2000 mg.
Daily administration
The method of treating retroviral infection further includes administering the compound or a pharmaceutically acceptable salt of it to a subject on a daily basis.
Discrete daily or weekly dosage amounts
The method includes administering the compound or a pharmaceutically acceptable salt to a subject at a specified dosage amount of about 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg.
Split daily dosing into multiple administrations
The daily dose is split into two to four doses per day.
HIV infection targeted treatment
The method is performed where the retroviral infection is specifically an HIV infection.
Combination therapy with specified HIV-targeting antiviral classes
The method further specifies that the one or more additional antiviral agents are selected from HIV-protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, fusion inhibitors, and maturation inhibitors.
Overall, the claim set is directed to treating retroviral infections with a therapeutically effective amount of a compound of the structure or a pharmaceutically acceptable salt, administered daily or weekly in a defined mg range, with dependents specifying daily administration, discrete dose amounts, split dosing, narrowing to HIV infection, and optional combination therapy using specified HIV-targeting antiviral classes.
Stated Advantages
Increased intracellular tenofovir-diphosphate (TFV-PP) levels and long intracellular half-life enabling lower dosages and infrequent dosing.
High potency versus tenofovir, including activity against NRTI-resistant HIV isolates.
Activity against XMRV.
In vitro transport studies indicate low apparent OAT1/OAT3 substrate potential versus tenofovir, relevant to nephrotoxicity.
Documented Applications
Treatment/prevention of retroviral infections in a subject, including HIV-1 and XMRV (gamma retrovirus).
Treatment/prevention of Hepatitis B viral infections (HBV) using phosphonate ester tenofovir prodrug compounds.
Topical/microbicide inhibition of sexual transmission of HIV, optionally with concurrent additional antivirals.
Interested in licensing this patent?