# Leptin Receptor Agonist as a Novel Prevention of Opioid Induced Respiratory Depression

> **NIH NIH R41** · ARREVUS, INC. · 2022 · $318,971

## Abstract

Opioid overdose kills 130 people in the United States every day according to the CDC/NCHS National Vital
Statistics System. The primary cause of death associated with opioids is opioid-induced respiratory
depression (OIRD). There is no FDA-approved OIRD prevention that maintains opioid analgesia.. Several high-
risk patient groups for non-naloxone-based OIRD prevention can be identified. By far the largest group includes
patients with underlying OSA, who require high doses of opioids for pain control post-surgery and/or post-injury
in the hospital settings. OSA is a very common disease affecting 34% of men and 17.4% of women in the US.
Greater than 50% of obese individuals have OSA and the prevalence of obesity in the US is nearly 40%, and
increasing. The overarching goal of our proposal to develop a novel OIRD preventive pharmaceutical and
validate it in a mouse model. We have shown that an adipocyte-produced hormone, leptin, which suppresses
appetite and increases metabolic rate, also stimulates breathing during sleep. Our laboratory extensively studies
sleep and breathing in mice. Leptin deficient obese ob/ob mice demonstrate hypoventilation and OSA, which
can be treated with leptin. We have also shown that mice with diet-induced obesity (DIO) develop OHS and
OSA, similar to obese humans, despite high plasma leptin level, indicating leptin resistance. We have shown
that if leptin is administered intranasally (IN) in DIO mice, the blood-brain barrier (BBB) can be
circumvented, central exposure to the hormone is facilitated, and hypoventilation and sleep apnea are
abolished. We have also shown that IN leptin prevents OIRD and that IN leptin does not reverse and may even
augment opioid analgesia. However, the mouse and human olfactory bulbs have significant anatomical
differences and response to IN leptin may differ between species. Leptin receptor agonists engineered to
penetrate the BBB are promising therapeutic candidates for OIRD. Dr. Laszlo Otvos developed such a potent
agonist, E1/Aca, which is superior to leptin for weight loss and metabolic dysfunction in mice and rats. We
established a collaboration with Arrevus, which holds a license on E1/Aca, and developed our STTR proposal.
We hypothesize that the LEPRb agonist E1/Aca will prevent OIRD in leptin resistant DIO mice without
reversing analgesia. In Aim 1, we will examine the effect of E1/Aca on fentanyl-induced OIRD using the fixed
dose of E1/Aca and escalating doses of fentanyl in Subaim 1A and escalating dose of E1/Aca and a fixed dose
of fentanyl in Subaim 1B. In Aim 2: we will examine the effect of E1/Aca on fentanyl analgesia. We hypothesize
that the target dose of E1/Aca identified from Aim 1 for OIRD will not decrease fentanyl analgesia in DIO mice.
Thus, the Phase I of our STTR will establish the efficacy of the leptin receptor agonist E1/Aca for
prevention of fentanyl OIRD in a mouse model.

## Key facts

- **NIH application ID:** 10476034
- **Project number:** 1R41DA056239-01
- **Recipient organization:** ARREVUS, INC.
- **Principal Investigator:** Carl Neil Kraus
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $318,971
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476034

## Citation

> US National Institutes of Health, RePORTER application 10476034, Leptin Receptor Agonist as a Novel Prevention of Opioid Induced Respiratory Depression (1R41DA056239-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10476034. Licensed CC0.

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