OX124 for Opioid Overdose Reversal Receives FDA Complete Response Letter

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The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) to Orexo for OX124, a high-dose naloxone nasal spray for opioid overdose reversal.¹

OX124 is a high dose proprietary naloxone formulation that can reverse an overdose or help sustain consciousness in an individual who has taken synthetic opioids, thanks to its rapid absorption and high bioavailability. Orexo submitted their New Drug Application for OX124 back in September 2023.²

The new CRL cites 2 requests: (1) another human factors study, in alignment with earlier conversations between Orexo and the FDA, and (2) additional technical data on the final commercial product. The latter of these requests is “unexpected,” says Orexo leadership. The FDA did not indicate a need for additional clinical or nonclinical studies.

"I am impressed by the vigour and agility of the teams in Sweden and the US in addressing FDA’s concerns from April regarding the instructions for use and our ability to complete a new human factors study shortly. However, I am surprised with the agency’s other requests with regards to additional technical data from final commercial product, but I am confident we can address this efficiently,” said Nikolaj Sørensen, president and CEO of Orexo. "We remain confident our powerful life-saving medication, OX124, can contribute to reducing the steep number of Americans who die from overdoses caused by the increasingly prevalent synthetic opioids. Me and my team are determined to continue taking the necessary actions to swiftly provide the FDA with the additional information.”

Orexo was aiming for a potential launch later this year or early 2025. Orexo received feedback from the FDA in April 2024, and since then, Orexo says it has worked to revise the product's usage instructions. Additionally, a new human factors study was successfully completed. Orexo also noted that its filing did include technical data from pilot-scale manufacturing, and it believed that this would be sufficient for approval.

In the study OX124-002, OX124 showed a significantly faster and higher absorption of naloxone compared with intramuscular dosing with an injection reference product. Additionally, in a previous exploratory clinical study (OX124-001), development formulations of OX124 demonstrated a more rapid absorption and higher bioavailability in healthy volunteers compared with the market leading naloxone rescue medication, even with the same dose as the comparator.

Efforts like the development of OX124 and the recent approval of Narcan for nonprescription, over-the-counter use are aimed at reducing the startling number of Americans who die from opioid overdose. From 2000 to 2014, the rate of overdoses involving opioids jumped by 200%; between 2013 to 2019, the synthetic opioid-involved death rate increased 1040%.^3,4

"This high-dose life-saving medication has the potential to curb the huge upturn in lethal overdoses seen over the past years and which is grounded in the wide spread of fentanyl," said Sørensen.²

References

1. Orexo shares new information on OX124, a high-dose naloxone rescue medication in development for opioid overdose. News release. July 16, 2024. Accessed July 18, 2024. https://www.prnewswire.com/news-releases/orexo-shares-new-information-on-ox124-a-high-dose-naloxone-rescue-medication-in-development-for-opioid-overdose-302198612.html

2. Orexo submits New Drug Application to FDA for OX124, a high-dose rescue medication for opioid overdose. News release. September 18, 2023. Accessed July 18, 2024. https://www.prnewswire.com/news-releases/orexo-submits-new-drug-application-to-fda-for-ox124-a-high-dose-rescue-medication-for-opioid-overdose-301930119.html

3. Rudd RA, Aleshire N, Zibbell JE, Gladden M. Increases in drug and opioid overdose deaths - United States, 2000–2014. Centers for Disease Control and Prevention. Accessed September 12, 2022. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6450a3.htm

4. Mattson CL, Tanz LJ, Quinn K, et al. Trends and Geographic Patterns in Drug and Synthetic Opioid Overdose Deaths - United States, 2013-2019. MMWR Morb Mortal Wkly Rep. 2021;70(6):202-207.