Advancing KNX100 for the treatment of opioid withdrawal: preclinical efficacy and toxicology, and a phase 1 clinical program.

Application Identifier: 364510
Application Project Title: Advancing KNX100 for the treatment of opioid withdrawal: preclinical efficacy and
toxicology, and a phase 1 clinical program.
Project Summary/Abstract
Kinoxis Therapeutics Pty Ltd is an Australian based company that has licensed intellectual property from the
University of Sydney, including several candidates for the treatment of substance use disorders. We have
developed a novel small molecule lead, KNX100, which is showing considerable promise in preclinical animal
models of a range of substance use disorders, including models of OUD, with particularly impressive efficacy
at reducing the severity of opioid withdrawal symptoms in mice. KNX100 was discovered from a phenotypic
screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin
system. KNX100 has a favorable pharmacokinetic and safety profile in testing thus far. To date, KNX100 has
undergone testing for efficacy signals in two rodent and two non-human primate species, with testing taking
place across multiple laboratories including National Institute on Drug Abuse (NIDA) commissioned
laboratories under the NIDA Medications Development Program.
The proposed activity under this funding opportunity is to progress the development of KNX100 in opioid use
disorder, with the specific indication being treatment of opioid withdrawal. The overall objective of the project
is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients
requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate
human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and
ultimately enable a New Drug Application to the FDA.
The company has developed a research plan which entails both a UG3 Phase and a UH3 Phase. For the UG3
Phase, the company plans to complete all the necessary IND enabling studies required for FDA approval to
administer KNX100 in a first in man, Phase 1 clinical study. The program includes additional testing of KNX100
in animal models of opioid withdrawal; scale up and manufacture of drug substance and drug product to
support both the non-clinical and clinical programs; a toxicology program to generate data to support the Phase
1 study; and the submission of an Investigational New Drug Application to the FDA.
Following the successful completion of the UG3 Phase, measured by the milestone of FDA Clearance of an IND
Application to a Commence a Phase 1 Study without a clinical hold, the company would then progress into the
UH3 Phase by completing a Phase 1 clinical program to establish the safety and tolerability of KNX100 when
dosed in humans.
The purpose of this NIH/NIDA Funding Opportunity Announcement (RFA-DA-19-002), for which this
application is being submitted, is to support the discovery and development of medications to prevent and treat
opioid use disorders (OUD) and overdose. The development of KNX100 offers an opportunity to provide a
more efficacious and/or safer alternative to the current only approved medication for opioid withdrawal,
lofexidine, and this application will accelerate the development toward this objective.

Grant Number: 5UH3DA048743-04
NIH Institute/Center: NIH
Principal Investigator: Hugh Alsop