Compositions and methods for treating an aggregation disease or disorder
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Publication Number
US-10751353-B2
Publication Date
2020-08-25
Expiration Date
Abstract
The present invention alleviates a sign or symptom of an aggregation disease or disorder by administering an aqueous formulation comprising trehalose.
Core Innovation
The invention relates to trehalose-only aqueous pharmaceutical formulations for rapid intravenous administration to alleviate signs and/or symptoms of aggregation diseases in a human subject. The disclosed approach emphasizes treating or alleviating symptoms associated with oculopharyngeal muscular dystrophy (OPMD), with mechanism centered on cellular uptake and retention following intravenous trehalose administration.
A central aspect is that the trehalose formulation is characterized by specific formulation constraints, including a pH of about 4.5 to 7.0 and endotoxin levels below 0.75 endotoxin units per mL. The formulation is also described with trehalose concentration and osmolality constraints, including osmolality about 280 to 330 mOsm/kg, supporting intravenous delivery with an administration completed within less than 120 minutes.
The disclosed rationale further states that rapid intravenous trehalose leads to cellular uptake and retention for about 48 to 72 hours and reduces intracellular protein aggregation, including aggregation associated with PABPN1. Preclinical rat pharmacokinetics are described as showing substantially higher muscle exposure relative to plasma after intravenous dosing, with longer muscle half-life and poor oral bioavailability.
The document also describes quality and safety-related aspects such as sterility/endotoxin testing results and a planned clinical study in OPMD evaluating safety, pharmacokinetics, and efficacy endpoints. Efficacy and function endpoints are described using dysphagia-related measures and muscle timed functional and strength assessments, and the clinical dosing is described as weekly administration of trehalose with infusion duration consistent with the rapid completion constraints.
Claims Coverage
The independent claim covers a method of treating selected neurodegenerative/aggregation-related diseases (or alleviating at least one associated symptom) in a human subject by intravenously administering a trehalose-only pharmaceutical formulation, with claim coverage focused on three core formulation constraints and one rapid administration constraint. Additional inventive features are provided mainly through dependent refinement of administration timing, dosing schedule, and formulation quantitative ranges.
Trehalose-only intravenous treatment of selected aggregation diseases
A method for treating a disease or disorder selected from SBMA, DRPLA, Pick's disease, CBD, PSP, Frontotemporal dementia, or parkinsonism linked to chromosome 17, or alleviating at least one symptom associated therewith, in a human subject, comprising intravenously administering a pharmaceutical formulation comprising trehalose as sole active ingredient.
Formulation pH constraint for trehalose-only IV formulation
The trehalose-only formulation has a pH about 4.5 to 7.0.
Endotoxin-limited trehalose-only IV formulation
The trehalose-only formulation contains less than 0.75 endotoxin units per mL.
Per-administration trehalose dose range with rapid completion
The trehalose-only formulation is administered at a per administration dose of between 5 to 50 grams trehalose, wherein the administration is completed within less than 120 minutes.
Shorter administration completion time
The method specifies that administration is completed within less than 90 minutes.
Trehalose concentration range in the pharmaceutical formulation
The pharmaceutical formulation has a trehalose concentration between about 0.1% (w/v) and about 50% (w/v).
Osmolality range for the trehalose formulation
The pharmaceutical formulation has an osmolality of about 280 to 330 mOsm/kg.
Once-weekly dosing schedule
The method specifies that the administering is done once weekly.
Targeting Progressive supranuclear palsy (PSP)
The method is for treating Progressive supranuclear palsy (PSP).
Overall, the claim set is centered on intravenously administering a trehalose-only pharmaceutical formulation to treat or alleviate symptoms of selected aggregation diseases, while meeting specified pH, endotoxin, and per-administration trehalose dose constraints together with rapid administration completion. Dependent claims further narrow administration completion time, trehalose concentration and osmolality ranges, dosing frequency, and specific target disease including PSP.
Stated Advantages
Reduces intracellular protein aggregation, including aggregation associated with PABPN1, after rapid intravenous trehalose.
Provides substantially higher muscle exposure relative to plasma after intravenous dosing, including longer muscle half-life.
Allows rapid intravenous administration with administration completion within less than 120 minutes, and in some refinements less than 90 minutes.
Documented Applications
A planned clinical study in OPMD evaluating safety, pharmacokinetics, and efficacy endpoints, including dysphagia-related measures and muscle timed functional and strength assessments, using weekly intravenous trehalose.
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