Daridorexant: Novel insomnia drug shows low abuse potential in comprehensive animal study

Significance 

The misuse and abuse of central nervous system (CNS)-active drugs is a significant public health challenge. Stimulants’, such as amphetamines, and sedatives’, like opioids and GABA(A) receptor agonists, misuse can lead to addiction, adverse health outcomes, and societal harm. Consequently, regulatory agencies, including the US Drug Enforcement Administration and the European Medicines Agency (EMA), require evaluations of the abuse potential of new CNS-active drugs as part of their approval process. Daridorexant is a novel dual orexin receptor antagonist (DORA), which was approved in 2022 in the United States and Europe for the treatment of insomnia. Unlike traditional sleep medications that most often act on GABA(A) receptors, DORAs function by selectively inhibiting wake-promoting orexin receptor signaling and can facilitate sleep without the euphoric effects typically associated with drugs of abuse. Despite these promising characteristics, the potential for misuse of any new CNS-active drug must be thoroughly investigated to ensure public safety. To this end, researchers led by Dr. Michel Steiner and Dr. Michael Toeroek-Schafroth from Idorsia Pharmaceuticals Ltd. in Switzerland alongside Dr. Maria Elena Giusepponi, Dr. Lisa Dacome, and Dr. Michela Tessari from Aptuit Srl, an Evotec Company in Italy, conducted a comprehensive assessment of daridorexant’s abuse potential using three established animal models: drug self-administration, drug discrimination, and physical dependence. These models were designed to investigate key aspects of drug abuse potential, including reinforcing effects, similarity to known drugs of abuse, and signs of physical dependence. The new study is now published in Journal of Psychopharmacology.

The research team performed the drug self-administration experiment to determine if daridorexant has reinforcing effects similar to those seen with known drugs of abuse. They used female Sprague Dawley rats, equipped with femoral vein catheters, that  were initially trained to self-administer cocaine, a well-established stimulant and positive reference drug. The rats were then divided into groups and underwent a substitution phase where cocaine was replaced with various doses of daridorexant or its vehicle. Throughout this phase, the researchers observed the number of active lever presses, a measure of drug-seeking behavior. The results showed that rats receiving daridorexant had significantly fewer active lever presses compared to those continuing on cocaine, indicating a lack of reinforcing effects. The responding of daridorexant-treated rats was similar to that of vehicle-treated rats, further supporting the conclusion that daridorexant does not sustain operant responding indicative of self-administration.

The authors afterward performed the drug discrimination experiments which can assess whether the interoceptive effects (i.e., bodily sensations) of daridorexant resemble those of zolpidem, a sleep medication with a history of abuse. To do this, the team trained rats to discriminate between zolpidem and its vehicle in a two-lever operant task. Following successful training, the rats were tested for generalization to various doses of daridorexant, lorazepam, and suvorexant, with the primary outcome being the percentage of responding on the zolpidem-appropriate lever and found that daridorexant did not cause stimulus generalization to zolpidem at any dose tested, which indicates that its interoceptive effects are distinct from those of zolpidem. In contrast, the benzodiazepine lorazepam produced partial to full generalization to zolpidem, which validated the sensitivity of the drug discrimination paradigm. Suvorexant, another DORA, also failed to generalize to zolpidem, and these results suggest that daridorexant, like other DORAs does not produce the same bodily sensations as zolpidem and reduces its potential for abuse.

The authors also conducted the physical dependence experiment, which can determine if chronic treatment with daridorexant leads to withdrawal symptoms upon abrupt discontinuation. To do this, the authors divided rats into four groups, and they treated them daily for 28 days with either daridorexant, its vehicle, or chlordiazepoxide (CDP), a benzodiazepine known for its dependence potential. They recorded different parameters including body weight, food consumption, body temperature, spontaneous locomotor activity, and neurobehavioral signs during and after the treatment period. According to the authors, the chronic treatment with daridorexant did not result in withdrawal symptoms or significant changes in physiological or neurobehavioral variables upon discontinuation. Rats treated with daridorexant maintained stable body weight and normal behavior throughout the treatment and withdrawal phases. In contrast, CDP-treated rats exhibited typical withdrawal symptoms, including reduced body weight, decreased food consumption, and increased neurobehavioral signs, confirming the sensitivity of the experimental setup. These results indicate that daridorexant does not induce physical dependence, further supporting its safe profile for therapeutic use.

In conclusion, Dr. Michel Steiner and colleagues’ findings on daridorexant’s abuse potential have significant clinical and public health implications. The study demonstrated that daridorexant, unlike traditional GABA(A) receptor sleep medications, does not show abuse potential in animals. This validates the safety profile of DORAs as a class, distinguishing them from other CNS-active drugs with higher risks of abuse and dependence. The comprehensive assessment met FDA and EMA requirements,  facilitating daridorexant’s approval and ensuring compliance with safety standards. Clinicians can prescribe daridorexant with greater confidence, knowing that it lacks the dependence risks of most traditional sedatives. Patients that are informed about daridorexant’s low abuse risk are more likely to adhere to their therapeutic regimen, improving insomnia management. The lower abuse potential of daridorexant also mitigates public health challenges associated with substance misuse and, thus, contributes to overall community well-being.

Daridorexant: Novel insomnia drug shows low abuse potential in comprehensive animal study - Medicine Innovates
3-D structural representation of daridorexant within the binding pocked of the orexin type 2 receptor (image by: Dr. Naomi Tidten, Idorsia Pharmaceuticals Ltd.)

About the author

Dr. Michel-Alexander Steiner is a senior director and group leader of preclinical CNS pharmacology at the Swiss pharma company Idorsia Pharmaceuticals Ltd. He is a biochemist by training and performed his PhD at the Max-Planck-Institute of Psychiatry in Munich, Germany. Before joining Idorsia, Dr. Steiner worked for several years at Actelion Pharmaceuticals Ltd., one of the most successful biotech companies of Europe. Besides daridorexant, he contributed to the preclinical profiling of many other advanced small molecule drug candidates that later entered human trials.

Reference 

Steiner MA, Toeroek-Schafroth M, Giusepponi ME, Dacome L, Tessari M. Abuse potential assessment of the dual orexin receptor antagonist daridorexant in rats. J Psychopharmacol. 2023 Dec;37(12):1249-1260. doi: 10.1177/02698811231215415.

Go To J Psychopharmacol.