Combination therapies for the treatment of viral infections
AssigneeFlagship Pioneering Innovations VI, LLC
InventorDavid Barry Kolesky
Life of this patent
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Abstract
The present disclosure relates to therapeutic agents and combinations thereof (e.g., pharmaceutical compositions) for the treatment of a viral infection in a subject, tissue or cell.
Claims64
A composition for use in treating a viral infection in a subject comprising a combination of a hypericin compound and an antiviral agent,
- wherein the molar amount of the hypericin compound in the combination is greater than the molar amount of the antiviral agent.
The composition for use of any one of the preceding claims, wherein the efficacy of the combination is at least X1-fold greater than the efficacy of the hypericin compound alone at the molar amount used in the combination, wherein X1 is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater.
The composition for use of any one of the preceding claims, wherein the efficacy of the combination is at least X1-fold greater than the efficacy of the antiviral agent alone at the molar amount used in the combination, wherein X1 is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater.
The composition for use of any one of the preceding claims, wherein the efficacy of the combination is at least X1-fold greater than the efficacy of the antiviral agent alone or the hypericin compound alone at the molar amount used in the combination, wherein X1 is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater.
The composition for use of any one of the preceding claims, wherein the molar amount of the hypericin compound in the combination comprises the molar concentration of the hypericin compound in the combination.
The composition for use of any one of the preceding claims, wherein the molar amount of the antiviral agent in the combination comprises the molar concentration of the antiviral agent in the combination.
The composition for use of any one of the preceding claims, wherein each of the hypericin compound and the antiviral agent is independently formulated as a pharmaceutical composition.
The composition for use of any one of the preceding claims, wherein the hypericin compound and the antiviral agent are formulated together as a pharmaceutical composition.
The composition for use of any one of the preceding claims, wherein the hypericin compound is a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6a, R6b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, halo, cyano, —ORA, —NRBRC, —C(O)NRBRC, —NRBC(O)RD, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R9;
- or
- R1a and R1b, R2a and R2b, R3a and R3b, R4a and R4b, R5a and R5b, or R6a and R6b is independently taken together with the atoms to which they are attached to form an oxo group;
- each of R7 and R8 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, halo, cyano, —ORA, —NRBRC, —C(O)NRBRC, —NRBC(O)RD, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R10;
- each of RA, RB, RC, and RD is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl;
- each of R9 and R10 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, halo, or cyano;
- the bond indicated by “═” is either present or absent, wherein if the bond is absent, the corresponding carbon atoms are independently attached to hydrogen, C1-C6 alkyl, or halo;
- and
- each “” is independently a single or double bond, according to valency.
The compound for use of any one of the preceding claims, wherein the hypericin compound is prepared synthetically or is extracted from a natural source (e.g., St. John's Wort).
The composition for use of any one of the preceding claims, wherein the hypericin compound is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.
The composition for use of any one of the preceding claims, wherein the composition comprises the hypericin compound in the absence of hyperforin, adhyperforin, or a pharmaceutically acceptable salt thereof.
The composition for use of any one of the preceding claims, wherein the hypericin compound is hypericin or a pharmaceutically acceptable salt thereof.
The composition for use of any one of the preceding claims, wherein the antiviral agent comprises a small molecule, antibody, peptide, or oligonucleotide.
The composition for use of any one of the preceding claims, wherein the antiviral agent is an agent that modulates a step in the viral life cycle.
The composition for use of any one of the preceding claims, wherein the antiviral agent is selected from the group consisting of an attachment inhibitor, post-attachment inhibitor, fusion inhibitor, entry inhibitor, uncoating inhibitor, protease inhibitor, polymerase inhibitor, nucleotide reverse transcriptase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, and integrase inhibitor.
The composition for use of any one of the preceding claims, wherein the antiviral agent comprises a nucleoside analog or a non-ribosomal peptide.
The composition for use of any one of the preceding claims, wherein the antiviral agent is compound of Formula (II):
- or a pharmaceutically acceptable salt thereof, wherein:
- Ring A is a heteroaryl or heterocyclyl, each of which is optionally substituted with R17 (e.g., a nucleobase or analog thereof);
- X is O or NR′;
- Z is O or S;
- each of R11 and R14 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, halo, or cyano;
- each of R12a, R12b, R13a, and R13b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, halo, cyano, —ORA, —NRBRC, —C(O)NRBRC, —NRBC(O)RD, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17;
- or
- R15 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;
- each of R16a and R16b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, —C(O)RD, —C1-C6 alkylene-C(O)O—C1-C6 alkyl, —C1-C6 alkylene-C(O)—C1-C6 alkenyl, —C1-C6 alkylene-C(O)O—C1-C6 heteroalkyl, —C1-C6 alkylene-C(O)O—C1-C6 haloalkyl, —C1-C6 alkylene-C(O)O—C1-C6 cycloalkyl, —C1-C6 alkylene-C(O)O—C1-C6 heterocyclyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkylene, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R18;
- R′ is hydrogen or C1-C6 alkyl;
- each of RA, RB, RC, and RD is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl;
- and
- each of R17 and R18 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, halo, or cyano.
The composition for use of any one of the preceding claims, wherein the antiviral agent targets an RNA virus.
The composition for use of any one of the preceding claims, wherein the antiviral agent is selected from remdesivir, sofosbuvir, or a pharmaceutically acceptable salt thereof.
The composition for use of any one of the preceding claims, wherein the antiviral agent is selected from remdesivir or a pharmaceutically acceptable salt thereof.
The composition for use of any one of the preceding claims, wherein the composition comprises the hypericin compound at a dosage of between 0.1 μM and 500 μM.
The composition for use of any one of the preceding claims, wherein the composition comprises the hypericin compound at a dosage of between 1 μM and 25 μM.
The composition for use of any one of the preceding claims, wherein the composition comprises the antiviral agent (e.g., remdesivir) at a dosage of between 0.01 μM and 25 μM.
The composition for use of any one of the preceding claims, wherein the composition comprises the antiviral agent (e.g., remdesivir) at a dosage of between 0.1 μM and 5 μM.
The composition for use of any one of the preceding claims, wherein the ratio of the amount of hypericin compound to the antiviral agent in the combination is between 200:1 to 1:1.
The composition for use of any one of the preceding claims, wherein:
- (i) the hypericin compound is hypericin or a pharmaceutically acceptable salt thereof;
- (ii) the antiviral agent is remdesivir or a pharmaceutically acceptable salt thereof;
- and
- (iii) the molar amount of the hypericin compound in the combination is between 20-fold and 5-fold greater than the molar amount of the antiviral agent (e.g., remdesivir).
The composition for use of any one of the preceding claims, further comprising an additional agent.
The composition for use of any one of the preceding claims, wherein the composition is formulated for use in a mammal (e.g., a human).
The composition for use of any one of the preceding claims, wherein the composition is formulated for use in a virally infected organ, tissue, or cell.
The composition for use of any one of the preceding claims, wherein the viral infection is a coronavirus infection.
The composition for use of any one of the preceding claims, wherein the viral infection is a SARS coronavirus (SARS-CoV) infection, MERS coronavirus (MERS-CoV) infection, or SARS-CoV-2 infection.
The composition for use of any one of the preceding claims, wherein the viral infection is a SARS CoV-2 infection.
A composition for use in treating a SARS CoV-2 infection in a cell or a subject, comprising a combination of (i) hypericin or a pharmaceutically acceptable salt thereof and (ii) remdesivir or a pharmaceutically acceptable salt thereof,
- wherein of the molar ratio of hypericin to remdesivir in the combination is between 50:1 to 1:1.
A composition for use in reducing the toxicity of an antiviral agent in a cell or subject comprising a combination of a hypericin compound and the antiviral agent,
- wherein the molar amount of the hypericin compound in the combination is greater than the molar amount of the antiviral agent.
A composition for use in reducing the toxicity of remdesivir in a cell or subject comprising a combination of (i) hypericin or a pharmaceutically acceptable salt thereof and (ii) remdesivir or a pharmaceutically acceptable salt thereof,
- wherein the molar ratio of hypericin to remdesivir in the combination is between 50:1 to 1:1, optionally wherein the molar ratio of hypericin to remdesivir in the combination is between 50:1 to 2:1.
A composition for use in reducing the virulence of a virus in a subject comprising a combination of a hypericin compound and remdesivir,
- wherein the amount of the hypericin compound and the amount of remdesivir are selected such that the molar concentration of the hypericin compound is greater than the molar concentration of remdesivir;
- wherein reducing the virulence comprises one or more of:
- (i) reducing the infection rate;
- (ii) reducing the doubling rate, e.g., amount of virus produced by an infected host cell;
- (iii) reducing the rate of viral DNA/RNA synthesis;
- (iv) reducing the rate of DNA/RNA mutations by a nucleic acid polymerase;
- (v) reducing the rate of virion packaging.
A composition for use in treating a SARS CoV-2 infection in a human subject comprising a combination of (i) hypericin or a pharmaceutically acceptable salt thereof and (ii) remdesivir or a pharmaceutically acceptable salt thereof, wherein:
- the molar ratio of hypericin to remdesivir in the combination is between 25:1 to 2:1, and
- the hypericin is provided in the combination in the absence of hyperforin, adhyperforin, or a pharmaceutically acceptable salt thereof.
A composition for use in reducing the effective antiviral dose of remdesivir in a cell or subject, comprising a combination of:
- (i) hypericin or a pharmaceutically acceptable salt thereof;
- and (ii) remdesivir or a pharmaceutically acceptable salt thereof,
- wherein the molar amount of the hypericin compound in the combination is greater than the molar amount of remdesivir.
A composition for use in improving the efficacy of remdesivir in a cell or subject having SARS CoV-2, comprising a combination of:
- (i) hypericin or a pharmaceutically acceptable salt thereof;
- and (ii) remdesivir or a pharmaceutically acceptable salt thereof,
- wherein the molar amount of the hypericin compound in the combination is greater than the molar amount of remdesivir.
Dependencies are inferred from the claim text.