Methods of treating hepatic encephalopathy
Inventors
Forbes, William • Merchant, Kunal • Bortey, Enoch • Shaw, Audrey
Assignees
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Publication Number
US-12285414-B2
Publication Date
2025-04-29
Expiration Date
Abstract
The application describes treatment of hepatic encephalopathy using gastrointestinal specific antibiotics. One example of a gastrointestinal specific antibiotic is rifaximin. The instant application also provides methods for determining if a subject has a neurological condition or hepatic encephalopathy by determining the critical flicker frequency and/or the venous ammonia level of the subject at two or more time points. The invention further provides methods for treating these subjects.
Core Innovation
The invention relates to methods of reducing the risk of hospitalization for a subject having hepatic encephalopathy by administering rifaximin. The subject has a Model for End-Stage Liver Disease score of between about 1 to 24, and rifaximin is administered daily for a period of 12 months or longer to thereby reduce the risk of hospitalization.
The disclosure includes GI-specific antibiotic treatment for preventing or treating hepatic encephalopathy, including breakthrough hepatic encephalopathy events and overt hepatic encephalopathy. Rifaximin is administered alone or in combination with lactulose, and the described outcomes include reductions in breakthrough overt hepatic encephalopathy risk and reductions in hepatic encephalopathy-related hospitalization frequency.
The document describes a randomized, double-blind, placebo-controlled study in subjects with recurrent, overt hepatic encephalopathy, with event-time analysis including Kaplan-Meier event-free curves and a Cox proportional hazards model. The report also describes diagnostic and prognostic monitoring using critical flicker frequency and venous ammonia levels, with reductions in venous ammonia and improvements in critical flicker frequency supporting efficacy.
Claims Coverage
The provided claim coverage includes one independent claim directed to reducing the risk of hospitalization in subjects with hepatic encephalopathy, with the main inventive features defined by rifaximin dosing and duration and subject eligibility based on Model for End-Stage Liver Disease score. The dependent claim refinements provided add lactulose, specify overt hepatic encephalopathy, constrain the MELD score to subranges, and define specific rifaximin dosing and a quantitative effectiveness threshold.
Reducing hospitalization risk in MELD 1 to 24 with daily rifaximin for 12 months or longer
A method of reducing the risk of hospitalization for a subject having hepatic encephalopathy by administering between about 1000 mg to about 1200 mg rifaximin daily to the subject for a period of 12 months or longer, wherein the subject has a Model for End-Stage Liver Disease score of between about 1 to 24, thereby reducing the risk of hospitalization.
At least 50% reduction in hospitalization visit frequency
Administering rifaximin in an amount sufficient to reduce the frequency of hospitalization visits by at least 50 percent compared to a subject not being administered rifaximin.
Combination with lactulose
Further administering lactulose.
MELD score less than or equal to 10
Performing the method on a subject whose MELD score is less than or equal to 10.
Overt hepatic encephalopathy
Characterizing that the hepatic encephalopathy is overt hepatic encephalopathy.
Rifaximin dosing of 550 mg twice daily
Including administering rifaximin at a dose of 550 mg twice daily.
The core claimed approach is reducing hospitalization risk in hepatic encephalopathy subjects with MELD score between about 1 and 24 by administering daily rifaximin in the range of about 1000 mg to about 1200 mg for 12 months or longer. The dependent refinements emphasize at least 50 percent reduction in hospitalization visit frequency, combination therapy with lactulose, overt hepatic encephalopathy, MELD less than or equal to 10, and rifaximin at 550 mg twice daily.
Stated Advantages
Reduces the risk of hospitalization in subjects having hepatic encephalopathy.
Reduces the risk of breakthrough overt hepatic encephalopathy events.
Reduces hepatic encephalopathy-related hospitalization frequency.
Improves associated clinical and objective measures, including Conn score, asterixis, ammonia, and critical flicker frequency.
Reduces HE-related hospitalization risk.
Reduces HE-caused hospitalization risk.
Fewer breakthrough overt hepatic encephalopathy episodes versus placebo.
Delayed worsening in Conn score and asterixis grade.
Reduced venous ammonia.
Improved critical flicker frequency (CFF).
Durable protection suggested by longer-term open-label extension.
Concomitant lactulose use does not modify efficacy.
Documented Applications
Preventing or treating hepatic encephalopathy in subjects, including reducing breakthrough hepatic encephalopathy and hepatic encephalopathy-related hospitalization, using GI-specific antibiotic therapy with rifaximin alone or with lactulose and monitoring via critical flicker frequency and venous ammonia.
Reducing the risk of hospitalization for subjects having hepatic encephalopathy by administering rifaximin daily for 12 months or longer in subjects with specified MELD score ranges.
Treatment of recurrent, overt hepatic encephalopathy in a randomized, double-blind, placebo-controlled study using rifaximin versus placebo.
Longer-term open-label treatment-extension follow-up to suggest durability of protection with maintained or improved Conn and asterixis profiles and low HE-related hospitalization rates.
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