Osanetant drug can have opposite effects on memory according to sexual differences

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A research team from the Institut de Neurociències at the Universitat Autònoma de Barcelona (INc-UAB) has showed that inhibition of the Tac2 neuronal circuit, involved in the formation of the memory of fear, has opposite effects according to sex on the ability to remember aversive events in mice, reducing it in male mice and increasing it in female mice.

It is the first time that a drug has been shown to produce this opposite effect on the memory of male and female mice. The study also shows that opposing molecular mechanisms and behaviors can occur in memory formation depending on sex. The study has been published in Nature Communications.

The research group on translational mechanisms of the memory of fear, led by Raül Andero, professor and researcher at ICREA, has been studying the functioning of fear memory for years to find treatments for pathologies associated with traumatic experiences, such as post-traumatic stress and phobias.

The research team had identified that the Tac2 circuit, located in the amygdala, could be temporarily blocked by the effect of a drug they are studying. This drug, Osanetant, was able to reduce the capacity to recall traumatic events in male mice. In the study, they discovered that this same drug produces the opposite effect in female mice, increasing their fear memory.

This opposite effect is explained by the fact that in blocking the Tac2 pathway, the drug interacts with the neuronal receptors of two sex hormones: testosterone in males and estrogen in females.

In addition, hormonal fluctuations during the oestrous cycle in female mice, equivalent to the menstrual cycle in women, vary the effects of the drug on the ability to remember aversive events.

“These results demonstrate the ability that hormones have to modulate the formation of fear memories, and show the need to consider sex differences and hormonal cycles in the design of pharmacological treatments for psychiatric disorders,” says Antonio Florido, INc-UAB predoctoral researcher and first author of the article.

In the field of neuroscience, only one study on females is published for every 5.5 on males. And research on Tac2 pathway has also been done mostly in males so far.

“Understanding how and why memory processes differ between sexes is key to designing treatments for fear disorders, especially considering that women are the ones who most often present these types of disorders. Some drugs that are already used may not have the expected effects on them,” says Raül Andero, the study coordinator..

“Our findings may help raise awareness of the need to do research differentiating by sex and promote basic and clinical studies that include the female sex,” he adds.

The drug studied is not new, but it is safe for use in humans. However, at the moment it is not being used to treat any disease. Dr. Andero’s group is now investigating its potential use in treating fear disorders differently by sex.

In this research, which has been carried out in collaboration with other INc-UAB research groups and the Hospital del Mar Medical Research Institute (IMIM), scientists show the importance of personalized medicine. “Mental health drugs that we have today, not only for memory-related disorders, are not specific enough and may be causing contrary effects to those desired,” they conclude.


March 1, 2021 – Acer Therapeutics Inc. (Nasdaq: ACER), a pharmaceutical company focused on the acquisition, development and commercialization of therapies for serious rare and life-threatening diseases with significant unmet medical needs, today reported financial results for the fourth quarter and full year ended December 31, 2020 and provided an update on the Company’s recent corporate developments.

“In spite of the challenges presented by a global pandemic in 2020, we continued to advance our existing programs while expanding our pipeline,” said Chris Schelling, CEO and Founder of Acer. “As a result, we anticipate a number of key milestones next quarter, including a proposed ACER-001 pre-NDA meeting with FDA, continuing to work toward a potential ACER-001 collaboration and license agreement with Relief Therapeutics pursuant to the existing option agreement between the companies, and a Type B meeting with the FDA to discuss a possible path forward for EDSIVO™. We are also working toward initiation of a Phase 2 clinical trial of osanetant in BRCA-positive patients with induced vasomotor symptoms in the fourth quarter of 2021, subject to successful IND filing and additional capital, and continuing to seek non-dilutive capital to advance emetine development.”

Fourth Quarter 2020 and Recent Highlights

 ACER-001
 oSigned an Option Agreement with Relief Therapeutics Holding AG on January 25, 2021 providing Relief with exclusivity until June 30, 2021 for the right to pursue a potential collaboration and license agreement for worldwide development and commercialization for ACER-001. In return, Acer received a $1.0 million upfront nonrefundable payment and a $4.0 million secured loan from Relief
 oAnnounced in February 2021 topline results from Acer’s bioequivalence trial in which ACER-001 showed similar relative bioavailability compared to BUPHENYL® (sodium phenylbutyrate) under fed conditions
 EDSIVO™ (celiprolol)
 oAnnounced in December 2020 publication by Swedish investigators of additional long-term data from COL3A1-positive vascular Ehlers-Danlos Syndrome (vEDS) patients in the European Journal of Vascular and Endovascular Surgery entitled “Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome” (https://www.ejves.com/action/showPdf?pii=S1078-5884%2820%2930930-8)
 oSubmitted a Type B meeting request to the FDA in February 2021 to discuss Acer’s proposed plan to collect additional data and provide confirmatory evidence in support of celiprolol’s potential benefit in treating COL3A1-positive vEDS patients

 ACER-801 (osanetant)
 oCompleted active pharmaceutical ingredient (API) manufacturing and advanced other development activities to support an Investigational New Drug Application (IND) submission
 Corporate
 oPromoted Jefferson Davis to Chief Business Officer in February 2021. A veteran life science executive and transaction specialist with over 25 years of experience in business and corporate development, Mr. Davis has led or supported over 40 transactions with an aggregate value of more than $2 billion across all major therapeutic platforms, including antibodies, small molecules, aptamers, gene therapy, vaccines, and proteins
 oEnded the fourth quarter with $5.8 million in cash and cash equivalents. Acer believes its cash position as of December 31, 2020, combined with an additional $3.2 million of net proceeds subsequently received from the sales of common stock under its ATM facility and through its equity line purchase agreement with Lincoln Park Capital, along with the $1.0 million nonrefundable payment and $4.0 million secured loan received from Relief Therapeutics following the signing of the ACER-001 Option Agreement, will be sufficient to fund its operations into the third quarter of 2021

Upcoming Milestones

 ACER-001
 oQ2 2021: Targeting a pre-New Drug Application (NDA) meeting with the FDA in the second quarter of 2021, assuming successful completion of the ongoing development activities
 oMid-2021: ACER-001 NDA submission for treatment of patients with Urea Cycle Disorders (UCDs) is anticipated in mid-2021, provided that no additional data is requested by the FDA during Acer’s pre-NDA meeting and ongoing development activities are successfully completed (including evaluation of long-term product stability data)
 EDSIVO™
 oQ2 2021: Obtain FDA feedback from a Type B meeting in the second quarter of 2021 regarding Acer’s proposed plan to collect additional data which, if discussions are successful and the collected data is sufficient, could potentially satisfy the substantial evidence of effectiveness needed to support a resubmission of the EDSIVO™ NDA (although neither EDSIVO™ NDA resubmission nor approval is assured)
 ACER-801 (osanetant)
 oQ3 2021: IND submission for osanetant is anticipated in the third quarter of 2021
 oQ4 2021: Initiation of a Phase 2 clinical trial of osanetant in BRCA-positive patients who have undergone a prophylactic bilateral salpingo-oophorectomy (PBSO) is expected in the fourth quarter of 2021, dependent upon successful IND filing and subject to additional capital
 ACER-2820 (emetine)
 oOngoing: Further advancement of the emetine program for infectious diseases, including COVID-19, is dependent on Acer’s ability to raise non-dilutive capital
 oOngoing: The Company believes that most of the emetine IND-enabling work is in progress or complete, and intends to minimize future emetine spending as it continues to work with federal agencies and private research organizations toward the goal of securing non-dilutive funding


More information: A. Florido et al. Sex differences in fear memory consolidation via Tac2 signaling in mice, Nature Communications (2021). DOI: 10.1038/s41467-021-22911-9

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