Compositions and methods for treating respiratory depression with fenfluramine

Patent metadata

Field	Value
Publication number	US-2020330406-A1
Application number	US-201916692968-A
Country	US
Kind code	A1
Filing date	Nov 22, 2019
Priority date	Jun 14, 2018
Publication date	Oct 22, 2020
Grant date	—

Abstract

5-HT receptor agonists are useful in the treatment of a variety of diseases. Provided herein are methods of treating and/or reducing the occurrence of respiratory depression caused by an opioid in a human patient or patient population using a 5-HT receptor agonist, such as, for example, a 5-HT4 agonist (e.g., fenfluramine). Methods of stimulating one or more 5-HT4 receptors in the brain of a patient undergoing treatment with an opioid, wherein the patient is at risk of respiratory depression, by administering a 5-HT4 agonist (e.g., fenfluramine) to a subject in need thereof are provided. Pharmaceutical compositions for use in practicing the subject methods are also provided.

First claim

1 .- 23 . (canceled)

24 . A method of treating respiratory depression in a human patient, comprising: administering to the patient a therapeutically effective dose of a 5-hydroxytryptamine receptor 4 agonist (5-HT 4 agonist); and
allowing the 5-HT 4 agonist to stimulate 5-HT 4 receptors in the patient, thereby treating respiratory depression caused by the opioid, barbiturate or benzodiazepine in the patient.

25 . The method of claim 24 , wherein the respiratory depression is caused by Sudden Unexpected Death in Epilepsy (SUDEP).

26 . A method of reducing incidence of respiratory depression caused by a toxin in a selected human patient population, comprising:
selecting a population of human patients exposed to the toxin and thereby at risk of respiratory depression; administering to the selected patient population a therapeutically effective dose of a 5-HT4 agonist; and allowing the 5-HT 4 agonist to stimulate 5-HT 4 receptors in the selected patient population, thereby reducing incidence of respiratory depression caused by the toxin in the patient population.

27 . The method of any of claim 26 wherein the respiratory depression is intensified by co-ingestion or co-administration of alcohol or other CNS depressants.

28 . The method of any of claim 26 , wherein the 5-HT 4 agonist is selected from the group consisting of fenfluramine, BIMU-8, Cisapride, Mosapride, Prucalopride, Renzapride, RS-67506, Tegaserod, Zacopride, Metoclopramide, and Sulpiride, or a pharmaceutically acceptable salt thereof.

29 . The method of claim 26 , wherein the 5-HT 4 agonist is fenfluramine, or a pharmaceutically acceptable salt thereof; and
wherein fenfluramine is administered in a therapeutically effective dose as an adjunctive therapeutic agent; and wherein the therapeutically effective dose of fenfluramine is selected from the group consisting of 0.2 mg/kg/day to 0.08 mg/kg/day up to a 30 mg maximum daily dose.

30 . The method of claim 29 , wherein the therapeutically effective dose of fenfluramine is administered in an oral liquid dosage form.

31 . The method of claim 26 , wherein the 5-HT 4 agonist has a characteristic selected from the group consisting of:
(a) inactive at the 5-HT2B receptor; (b) a neutral agonist of the 5-HT2B receptor; and (c) an inverse agonist of the 5-HT2B receptor 5-HT2B receptor.

32 . The method of claim 31 , wherein the patient exhibits a significantly higher responder rate compared with placebo, the method further comprising:
repeating the administering over a period of days until the patient exhibits a ≥40% reduction from baseline in occurrence of respiratory depression.

33 . The method of claim 31 , wherein the patient exhibits at least a ≥50% reduction in occurrence of respiratory depression.

34 . The method of claim 31 , wherein the patient exhibits at least a ≥75% reduction in occurrence of respiratory depression.

35 . The method of claim 31 , wherein the patient exhibits at least a ≥90% reduction in occurrence of respiratory depression.

36 . The method of claim 31 , wherein the patient completely free of an occurrence of respiratory depression.

37 . The method of claim 24 , wherein the 5-HT 4 agonist is fenfluramine or a pharmaceutically acceptable salt thereof.

38 . The method of claim 24 , wherein the 5-HT 4 agonist is fenfluramine.

Assignees

• Zogenix International Ltd

Inventors

• Galer Bradley S
• Faingold Carl L
• Martin Parthena

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P11/16

  Central respiratory analeptics · CPC title

• A61K31/137 Primary

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title