ACER-801 (osanetant) for Acute Stress Disorder (ASD) and Post-traumatic Stress Disorder (PTSD)

ACER-801 (osanetant) for Acute Stress Disorder (ASD) and Post-traumatic Stress Disorder (PTSD)

ACER-801 (osanetant) is a novel, non-hormonal, neurokinin 3 receptor (NK3R) antagonist that could offer a potential treatment option in patients with Acute Stress Disorder (ASD) and Post-traumatic Stress Disorder (PTSD) by blocking a critical fear/stress sensitization step in the brain.1,2,3 Acute stress disorder refers to the body’s immediate response to trauma, whereas PTSD is defined as the long-term effects of trauma. While the role of the NK3R pathway in the hypothalamus to manage thermoregulation is well-established in clinical trials, our evaluation of osanetant in these indications will provide an opportunity to explore a different mechanism of action for the drug candidate.

In December 2018, we entered into an exclusive license agreement with Sanofi to acquire worldwide rights to ACER-801. Acer has also entered into an agreement with Emory University for an exclusive worldwide license to US Patent No. 10,314,835, US Application 15/320,952, and European Patent No. EP3160469 covering certain methods of treating or preventing PTSD with osanetant.

According to the National Center for PTSD, in the US about 6 of every 10 men (or 60%) and 5 of every 10 women (or 50%) experience at least one trauma in their lives leading to about 12 million adults in the U.S. have PTSD during a given year.4 In the US alone, one-third of emergency department visits are for evaluation after trauma exposures and up to 20% of people who have experienced a traumatic event will develop PTSD.1

Rationale for ACER-801 (osanetant) Evaluation in Post-Traumatic Stress Disorder
Studies conducted at Emory University screened thousands of genes that were activated in the brains of mice following fear conditioning events. The top gene identified was Tac2, which is responsible for the production of the peptide, Neurokinin B (NKB), in mice. The researchers showed that the Tac2 gene, expressed by neurons specifically within the amygdala, is required for modulating fear memories, and that NKB, and its specific receptor, NK3R, are also involved in the consolidation of fear memories. By administering the potent and specific NK3R antagonist, osanetant, they were able to block fear memory consolidation shortly after exposure to a trauma, potentially providing a novel therapeutic approach for disorders with altered fear learning such as PTSD.2

The Tacr3 gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, Neurokinin B (NKB), which is encoded by the Tac3 (human) gene. The role of NKB-NK3R in growth and reproduction has been extensively studied, but NKB-NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system.5  In animal models, Tac2 (mice) mRNA levels are rapidly up-regulated during fear consolidation 30 minutes after fear conditioning, and subsequent NKB-NK3R activation can lead to over stress sensitization and the consolidation of fear,6 and treatment with osanetant has been shown to block a critical fear/stress sensitization step in the brain.1,2,3 An effective therapeutic to reduce acute and persistent/long-term psychological and somatic symptoms would fulfill a large unmet need.

ACER-801 Registration Plan for ASD and PTSD
In October 2022, following our announced expansion of our ACER-801 program into ASD and PTSD, we reported that the University of North Carolina Institute for Trauma Recovery has been awarded a $3 million grant from the Department of Defense to investigate the potential of ACER-801 to reduce the frequency and severity of acute stress disorder and post-traumatic stress disorder.

The proposed Osanetant After Stress to Increase recovery Success (OASIS) trial will examine the safety and efficacy of ACER-801 to reduce acute stress response symptoms, post-traumatic stress disorder symptoms and behavioral changes among patients presenting to the emergency department after a motor vehicle collision. It is intended to enroll a total of 180 subjects who will be randomized in the emergency department, to receive a low or high dose of ACER-801 or placebo in the emergency department and be discharged with a two-week supply of study drug. Participating sites would include Washington University in St. Louis, University of Massachusetts Chan Medical School, Rhode Island Hospital, University of Florida College of Medicine – Jacksonville, and Indiana University School of Medicine. Initiation of patient enrollment in the proposed investigator-sponsored OASIS trial is anticipated in Q2 2023.

ACER-801 is an investigational drug in the U.S. and is not currently FDA-approved for any indication. There is no guarantee that this product candidate will receive regulatory authority approval in any territory or become commercially available for any indications.

References

  1. Sidran Institute.  Traumatic Stress Education & Advocacy Fact Sheet.
  2. Andero R, Dias BG, Ressler KJ. A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation. Neuron. 2014;83(2):444-454
  3. Andero R, Daniel S, Guo JD, et al. Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning. Neuropsychopharmacology. 2016;41(11):2714-2722
  4. National Center for PTSD.  How Common is PTSD in Adults?
  5. Zhang et al. Tacr3/NK3R: Beyond Their Roles in Reproduction. ACS Chemical Neuroscience 2020 11 (19), 2935-2943
  6. Al Abed et. Al, Biological Psychiatry 2021
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