Everyone here at the Hypersomnia Foundation is always excited when researchers and pharmaceutical companies include IH as a part of their clinical trials and research. With each clinical trial and research project, we grow ever closer to more effective treatments for IH, and, hopefully, someday a cure. The latest clinical trial is taking place in Finland, and is being operated by Umecrine Cognition. The medicine they are testing on IH patients, GR3027, was originally developed to reverse the adverse effects of liver failure on sleep and cognition.
Early in October of 2017, Umecrine Cognition (https://www.umecrinecognition.com) announced some very exciting news for the hypersomnia community – that they were expanding their study of a newly developed medicine to idiopathic hypersomnia!1 The company announced successful procurement of 20 million Swedish Krona (SEK) (~ $2.5 million US) in venture capital for an exploratory study in IH.1 Umecrine’s lead compound, referred to as GR3027, is an antagonist at GABAA receptors (GABAARs).
The novelty of GR3027 comes from: 1) its not being a traditional psychostimulant or wake-promoting drug; and 2) from its action at a location on the GABAAR where naturally occurring (i.e., endogenous) substances known as neurosteroids bind, as opposed to the traditional benzodiazepine binding site targeted by the more widely known antagonist flumazenil. Because GR3027 acts on the more natural binding site, it may be a more effective antagonist than flumazenil, which is actually a weak agonist, especially at higher doses. Thus, whereas flumazenil’s binding to the GABAAR may benefit wakefulness by interfering with the binding of naturally occurring enhancers of GABAARs, it might also briefly worsen sleepiness due to its weak activation of GABAARs.
GR3027 was originally developed with the intention to reverse the hypersomnolence and impairments in cognition that occur in the clinical setting of liver failure – aka, hepatic encephalopathy.1 Umecrine’s initial rationale to focus upon the clinical entity of hepatic encephalopathy came from a considerable converging literature that naturally occurring ‘endozepines’ accumulate when one’s liver fails, and that these ‘endozepines’ ultimately are responsible for reducing consciousness – namely, they impair cognition and promote sleep and daytime sleepiness.2,3 In fact, compelling placebo-controlled clinical trial data show the benefits of flumazenil on hepatic encephalopathy.4
In July 2015, researchers including those involved with Umecrine Cognition, published a study of GR3027 in rats with hepatic encephalopathy: “We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids…”5
In November 2016, Umecrine Cognition released positive phase 1b (i.e., an ‘early’ trial in humans exploring the safety and tolerability of a new drug and amounts of that drug that are attained in the blood and how it is metabolized by the body) data for GR3027 for the treatment of hepatic encephalopathy.6 “The results of a recently finished phase 1b-study show that GR3027 is tolerated well, does not cause any dosage limited side effects and has a favourable pharmacokinetic profile.”1
Given that the spinal fluids of many patients with idiopathic hypersomnia (IH) have an ‘endozepine’-like ability to enhance GABAAR function, that such activity can be reversed by flumazenil in vitro (i.e., a biological site outside of the body), and that flumazenil can benefit wakefulness in a substantial number of IH patients,7,8 Umecrine Cognition has expanded their research of GR3027 to include IH. This underscores the potential power in studying disorders which share several, or many, symptoms in common with IH. Visible disease-related signs and symptoms are referred to as a ‘phenotype’, and when closely mimicked by what might otherwise be thought to be a different ‘disease’, this other disease is said to represent a ‘phenocopy’ of the other. Because hepatic encephalopathy in many respects phenocopies IH, it suggests that a common cause and biology may explain their shared symptoms. Ultimately, then, GR3027, which was initially intended to treat hepatic encephalopathy, holds great promise in helping to treat IH.
Now, phase 2a trials (a phase in which assessment of a new drug’s potential benefit in treating a disorder is initially explored) of GR3027 in IH are underway in Finland.9 In fact, Umecrine Cognition has just announced the first IH patient joining their phase 2a trial, noting that the “objectives of the study… are to assess the safety and pharmacokinetics, and to evaluate the exploratory efficacy of GR3027 in patients with idiopathic hypersomnia.”10 This part of the study “includes an open-label part to assess safety, tolerability and pharmacokinetics of a single oral GR3027 dose in six female patients with IH…”10 It will be followed by Part B, which will be “a prospective, double-blind, randomized, placebo-controlled crossover study in male and female IH patients… Part B will enroll up to 14 male and female IH patients to assess safety, tolerability, exposure, and preliminary efficacy of multiple oral doses of GR3027.”10
We at the Hypersomnia Foundation look forward to the results of these ongoing phase 2 trials and remain excited that IH is on the radar of researchers and an increasing number of pharmaceutical company partners, intent on discovering novel medications to treat this often-disabling condition. We plan to keep the HF community up-to-date as we learn more about this exciting new avenue of investigation, including the results of Umecrine Cognition’s sponsored trial in IH.
By David Rye, MD, PhD, Chairperson, HF Scientific Advisory Board
- 2015 World J Gastroenterol. Endozepine-4 levels are increased in hepatic coma. https://www.ncbi.nlm.nih.gov/pubmed/26290636
- 2009 Metab Brain Dis. Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy. https://www.ncbi.nlm.nih.gov/pubmed/19082698
- 2015 Am J Physiol Gastrointest Liver Physiol. GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556948/
- 2016 J Clin Sleep Med. Flumazenil for the Treatment of Refractory Hypersomnolence: Clinical Experience with 153 Patients. https://www.ncbi.nlm.nih.gov/pubmed/27568889