STOCKHOLM/UMEÅ - 3 November, 2016. Karolinska Development's portfolio company Umecrine Cognition AB, today announces positive top-line results from its Phase 1 first in human clinical trial with GR3027, a novel orally active GABAA receptor modulating steroid antagonist, in development for treatment of hepatic encephalopathy (HE) in patients with liver cirrhosis. The study demonstrated that GR3027 was safe and well tolerated, and also showed CNS target engagement.
Details from the Umecrine Cognition press release follow:
“We are very encouraged by the pharmacodynamic effect of GR3027 in our Phase 1 trials, along with its favorable safety and tolerability profile,” said Magnus Doverskog, CEO of Umecrine Cognition. “These findings show that oral GR3027 reaches the brain target with an expected mechanism of action and combined with our previous pre-clinical results [1] support our belief that GR3027 could be an attractive new therapy for patients with liver cirrhosis and hepatic encephalopathy.”
Victor Drvota, Chief Investment Officer at Karolinska Development, said: “Umecrine Cognition’s strong early clinical results, together with its recent financing round, has placed the company in an excellent position to advance GR3027 into the next clinical studies needed to establish clinical proof of concept, a value inflection point.”
Umecrine Cognition’s lead candidate GR3027 is designed to reduce GABAA receptor mediated inhibition of brain function by antagonizing endogenous inhibitory neurosteroids such as allopregnanolone. Enhanced GABAA receptor mediated signaling is a key driver for the neurological symptoms associated with HE. In the current trial, GR3027 was found to be well tolerated with no serious adverse events reported and with dose proportional pharmacokinetics. Assessment of Saccadic Eye Velocity and self-rated sedation after a challenge with allopregnanolone showed evidence that orally administered GR3027 antagonizes neurosteroid modulation of GABAA receptor function.
The primary objectives of the study were to evaluate the safety and tolerability of GR3027 after single dose administration in healthy volunteers and to identify the Maximum Tolerated Dose (MTD) or the Study Maximal Dose (SMD), if the MTD was not reached. The secondary objectives were to determine the single oral dose PK characteristics of GR3027 in healthy volunteers and to evaluate the capacity of GR3027 to antagonize allopregnanolone-induced activation of GABAA as determined by its pharmacodynamic effects on Saccadic Eye Velocity (SEV) and self-rated sedation.
In the first part, 48 subjects were randomized to receive either GR3027 or placebo (6:2) at doses ranging from 1 mg to 200 mg. None of the pre-specified dose escalation stopping criteria were obtained and GR3027 was found to be well tolerated throughout the dose range up to the SMD of 200 mg. The pharmacokinetic profile obtained displayed dose linearity over the dose range applied.
In the second part of the study, 18 subjects were randomized in a three-part cross-over design to receive either GR3027 at 3 mg (low dose) or 30 mg (high dose), or placebo. As expected, allopregnanolone administration decreased SEV in the placebo group. Prespecified statistical analysis of the difference between treatment groups with GR3027 and placebo showed a significant improvement with GR3027 in the high dose group (p=0.03; Wilcoxons Signed Rank Test). The results also provide evidence that the impaired self-rated sedation produced by allopregnanolone was also improved by GR3027.
The company plans to announce further details and data of the trial at the 9th International Meeting – Steroids and Nervous System in Torino, Italy (February 11-15, 2017).
“We are very encouraged by the pharmacodynamic effect of GR3027 in our Phase 1 trials, along with its favorable safety and tolerability profile,” said Magnus Doverskog, CEO of Umecrine Cognition. “These findings show that oral GR3027 reaches the brain target with an expected mechanism of action and combined with our previous pre-clinical results [1] support our belief that GR3027 could be an attractive new therapy for patients with liver cirrhosis and hepatic encephalopathy.”
Victor Drvota, Chief Investment Officer at Karolinska Development, said: “Umecrine Cognition’s strong early clinical results, together with its recent financing round, has placed the company in an excellent position to advance GR3027 into the next clinical studies needed to establish clinical proof of concept, a value inflection point.”
Umecrine Cognition’s lead candidate GR3027 is designed to reduce GABAA receptor mediated inhibition of brain function by antagonizing endogenous inhibitory neurosteroids such as allopregnanolone. Enhanced GABAA receptor mediated signaling is a key driver for the neurological symptoms associated with HE. In the current trial, GR3027 was found to be well tolerated with no serious adverse events reported and with dose proportional pharmacokinetics. Assessment of Saccadic Eye Velocity and self-rated sedation after a challenge with allopregnanolone showed evidence that orally administered GR3027 antagonizes neurosteroid modulation of GABAA receptor function.
The primary objectives of the study were to evaluate the safety and tolerability of GR3027 after single dose administration in healthy volunteers and to identify the Maximum Tolerated Dose (MTD) or the Study Maximal Dose (SMD), if the MTD was not reached. The secondary objectives were to determine the single oral dose PK characteristics of GR3027 in healthy volunteers and to evaluate the capacity of GR3027 to antagonize allopregnanolone-induced activation of GABAA as determined by its pharmacodynamic effects on Saccadic Eye Velocity (SEV) and self-rated sedation.
In the first part, 48 subjects were randomized to receive either GR3027 or placebo (6:2) at doses ranging from 1 mg to 200 mg. None of the pre-specified dose escalation stopping criteria were obtained and GR3027 was found to be well tolerated throughout the dose range up to the SMD of 200 mg. The pharmacokinetic profile obtained displayed dose linearity over the dose range applied.
In the second part of the study, 18 subjects were randomized in a three-part cross-over design to receive either GR3027 at 3 mg (low dose) or 30 mg (high dose), or placebo. As expected, allopregnanolone administration decreased SEV in the placebo group. Prespecified statistical analysis of the difference between treatment groups with GR3027 and placebo showed a significant improvement with GR3027 in the high dose group (p=0.03; Wilcoxons Signed Rank Test). The results also provide evidence that the impaired self-rated sedation produced by allopregnanolone was also improved by GR3027.
The company plans to announce further details and data of the trial at the 9th International Meeting – Steroids and Nervous System in Torino, Italy (February 11-15, 2017).
