Methods of treating erythropoietic protoporphyria or x-linked protoporphyria with bitopertin
AssigneeDisc Medicine, Inc.
InventorsMelanie Chin, William Jacob Savage, John Quisel, John Chapin
Life of this patent
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Abstract
The present disclosure is directed to methods of using bitopertin for preventing or treating erythropoietic protoporphyria (EPP) and/or X-linked protoporphyria (XLPP), and related syndromes thereof.
Claims221
A method of treating erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLPP) comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks thereby reducing any one of i) the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more, or ii) reducing alanine aminotransferase (ALT) levels in the subject by at least 5%.
A method of treating EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks thereby resulting in a statistically significant improvement in pain-free light exposure in the subject.
A method of increasing sunlight tolerance in a subject with EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks thereby reducing any one of i) the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more, or ii) reducing alanine aminotransferase (ALT) levels in the subject by at least 5%.
A method of reducing liver damage in a subject with EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks thereby reducing any one of i) the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more, or ii) reducing alanine aminotransferase (ALT) levels in the subject by at least 5%.
A method of reducing protoporphyrin IX levels in a subject with EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks thereby reducing any one or both of i) the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more, or ii) reducing alanine aminotransferase (ALT) levels in the subject by at least 5%.
A method of treating erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLPP) in a subject in need thereof comprising
- a) administering 30 mg of bitopertin to the subject for at least 14 days;
- and
- b) administering 60 mg of bitopertin to the subject for a treatment period of at least 17 weeks;
- thereby reducing any one or both of i) the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more, or ii) reducing alanine aminotransferase (ALT) levels in the subject by at least 5%.
A method of treating EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks wherein the subject's heme and hemoglobin levels are maintained in comparison to reduced levels of heme and hemoglobin observed in a healthy subject administered bitopertin.
A method of treating EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for at least 17 weeks wherein the subject maintains liver function.
A method of treating EPP comprising administering 60 mg of bitopertin to a subject age 12 and older in need thereof for at least 17 weeks thereby resulting in one or more of the following:
- a. a reduction in PPIX levels;
- b a reduction in the rate of phototoxic reactions;
- c. an increase in average time of pain-free light exposure;
- d. an increase in average time to prodrome;
- e. an increase in proportion of prodrome-free weekly light exposure challenges;
- f. an increase in mean cumulative total time in light without pain;
- g. an improvement in the EPP Impact Questionnaire (EPIQ);
- h. an improvement in the Patient Global Impression of Pain (PGIC);
- and
- i. an improvement in the Patient Global Impression of Severity (PGIS).
A method of treating EPP comprising administering 60 mg of bitopertin to a geriatric subject in need thereof for at least 17 weeks thereby resulting in one or more of the following:
- a. a reduction in PPIX levels;
- b. a reduction in the rate of phototoxic reactions;
- c. an increase in average time of pain-free light exposure;
- d. an increase in average time to prodrome;
- e. an increase in proportion of prodrome-free weekly light exposure challenges;
- f. an increase in mean cumulative total time in light without pain;
- g an improvement in the EPP Impact Questionnaire (EPIQ);
- h. an improvement in the Patient Global Impression of Pain (PGIC);
- and
- i. an improvement in the Patient Global Impression of Severity (PGIS).
The method of any preceding claim, wherein the 60 mg of bitopertin is administered as two 30 mg doses.
The method of any preceding claim, wherein the bitopertin is administered once daily.
A method of treating EPP or XLPP in a subject in need thereof comprising administering to the subject a daily therapeutically effective dosage of bitopertin for a treatment period of at least 6 weeks, wherein pain free light exposure is increased to 5 or more hours compared to observed pain free light exposure in treatment with placebo.
A method of treating EPP or XLPP in a subject comprising administering a daily therapeutically effective dosage of bitopertin for a treatment period of at least 17 weeks, wherein whole blood PPIX is decreased and no dose dependent decrease in hemoglobin is observed compared to treatment in a subject without EPP.
A method of treating EPP or XLPP in a pediatric subject comprising administering a therapeutically effective dosage of bitopertin.
The method of any preceding claim, wherein the amount of or therapeutically effective dosage of bitopertin is modified for concomitant use with one or more CYP3A4 inhibitors.
The method of any preceding claim, wherein the subject has hepatic impairment, and wherein the subject is administered a modified amount of or modified therapeutically effective dosage of 30 mg of bitopertin once daily.
The method of claim, wherein the mild hepatic impairment is classified based upon the Child-Pugh scoring system.
The method of any preceding claim, wherein a median maximum pain score due to phototoxic reactions over the treatment period is reduced.
The method of any preceding claim, wherein a number of phototoxic reactions over the treatment period is reduced.
The method of any preceding claim, wherein one or more complications of EPP or XLPP are treated or prevented.
The method of any preceding claim, wherein the subject has EPP.
The method of any preceding claim, wherein the bitopertin is administered orally.
The method of any preceding claim, wherein the bitopertin is formulated as an immediate release tablet.
The method of any preceding claim, wherein the subject does not experience changes in skin pigmentation.
The method of any preceding claim, wherein the subject experiences less than 5% of adverse events associated with anemia.
The method of any preceding claim, wherein the subject experiences less than 5% of adverse events associated with the central nervous system (CNS).
The method of any preceding claim, wherein the administration ameliorates hepatic toxicity.
The method of any preceding claim, wherein the administration reduces the incidence of hepatobiliary disease.
The method of any preceding claim, wherein the administration reduces the progression of hepatobiliary disease.
The method of any preceding claim, wherein the subject's PPIX levels decrease by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the subject's heme levels decrease no more than 10%.
The method of any preceding claim, wherein the subject's PPIX levels decrease by at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%) and the subject's hemoglobin levels decrease no more than 10%.
The method of any preceding claim, wherein the subject's heme levels decrease no more than 10%.
The method of any preceding claim, wherein the subject's PPIX levels decrease while the subject's heme levels are substantially maintained.
The method of any preceding claim, wherein the subject's hemoglobin levels decrease no more than 10%.
The method of any preceding claim, wherein the subject's PPIX levels decrease while the subject's hemoglobin levels are substantially maintained.
The method of any preceding claim, wherein the subject has increased free-protoporphyrin IX levels in erythrocytes.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the erythrocytes of the subject.
The method of any preceding claim, wherein the method decreases free-protoporphyrin IX levels in the subject.
The method of any preceding claim, wherein the method decreases free-protoporphyrin IX levels in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).
The method of any preceding claim, wherein the subject has increased protoporphyrin IX levels in stool.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in stool of the subject.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the stool of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).
The method of any preceding claim, wherein protoporphyrin IX (PPIX) synthesis is inhibited in vivo.
The method of any preceding claim, wherein the subject's plasma porphyrin fluoresces at a peak of 634 nm when illuminated with blue light (e.g., 400-420 nm light).
The method of any preceding claim, wherein the subject's plasma porphyrin fluoresces at a peak between 626 nm and 634 nm when illuminated with blue light (e.g., 400-420 nm light).
The method of any preceding claim, wherein the subject's skin porphyrin fluoresces at a peak of 632 nm when illuminated with blue light (e.g., 400-420 nm light).
The method of any preceding claim, wherein the subject's skin porphyrin fluoresces at a peak between 626 nm and 634 nm when illuminated with blue light (e.g., 400-420 nm light).
The method of any preceding claim, wherein the subject has increased protoporphyrin IX levels in the skin.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).
The method of any preceding claim, wherein the subject has greater than 0.2 FluoDerm Units (FDU) of protoporphyrin IX levels in the skin.
The method of any preceding claim, wherein the subject has greater than 1.0 FDU of protoporphyrin IX levels in the skin.
The method of any preceding claim, wherein the subject has between 1.0 FDU and 2.5 FDU of protoporphyrin IX levels in the skin.
The method of any preceding claim, wherein the subject has greater than 2.5 FDU of protoporphyrin IX levels in the skin.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject to less than 0.5 FDU.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject to less than 1.0 FDU.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject to less than 1.5 FDU.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject to less than 2.0 FDU.
The method of any preceding claim, wherein the method decreases protoporphyrin IX levels in the skin of the subject to less than 2.5 FDU.
The method of any preceding claim, wherein zinc protoporphyrin IX (ZPPIX) synthesis is inhibited in vivo.
The method of any preceding claim, wherein 5-aminolevulinic acid (5-ALA) synthesis is inhibited in vivo.
The method of any preceding claim, wherein the subject in need thereof is 12 years and older.
The method of any preceding claim, wherein the total pain-free time in light of the subject increases as compared to the total pain-free time in light prior to treatment.
A method of treating liver disease associated with EPP or XLPP in a subject comprising administering 60 mg of bitopertin to a subject to a subject in need thereof for a treatment period of at least four weeks.
A method of treating protoporphyrin IX (PPIX) induced liver damage comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least four weeks.
A method of treating hepatopathy comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least four weeks.
A method of decreasing liver protoporphyrin IX concentrations comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least four weeks.
A method of reducing hepatobiliary biomarkers of liver damage comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least four weeks.
The method of any one of claims153-168, wherein the method reduces GGT concentrations in the subject by at least 15%.
The method of any one of claims153-169, wherein the method reduces serum total bilirubin (TBR) concentrations in the subject by at least 5%.
The method of any one of claims153-170, wherein the method reduces serum TBR concentrations in the subject by at least 10%.
The method of any one of claims153-171, wherein the method reduces serum TBR concentrations in the subject by at least 15%.
A method of increasing sunlight tolerance in a subject with EPP or XLPP comprising administering to the subject 60 mg of bitopertin for a treatment period of at least 17 weeks resulting in a statistically significant increase in sunlight tolerance without statistically significant abuse potential.
A method of treating EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks thereby resulting in a statistically significant improvement in pain-free light exposure in the subject without statistically significant abuse potential.
A method of reducing liver damage in a subject with EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks, thereby reducing the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more without statistically significant abuse potential.
A method of reducing protoporphyrin IX levels in a subject with EPP or XLPP comprising administering 60 mg of bitopertin to a subject in need thereof for a treatment period of at least 17 weeks, thereby reducing the rate of phototoxic reactions compared to the rate observed in treatment with placebo by 75% or more without statistically significant abuse potential.
The method of any one of claims 1-212, wherein administration of bitopertin does not induce a statistically significant abuse potential in the subject.
Dependencies are inferred from the claim text.