Enabling Rapid Drug Warming to Near-Ambient Temperatures for Immediate Use Post-Refrigeration with the Empaveli (pegcetocoplan) Injector

Introduction:

In the administration of refrigerated drug products for large-volume subcutaneous (SC) injections, a key preliminary step is warming the drug from refrigeration to room temperature, traditionally taking 15 to 45 minutes. For EMPAVELI, the first C3 complement inhibitor approved to treat Paroxysmal Nocturnal Hemoglobinuria (PNH), the standard protocol requires warming the vial for at least 30 minutes before injection. Although a 30-minute warming period might seem minor, it cumulatively adds significant time delays across patients, translating to 52 hours of lost time annually per patient. However, drug warming is an important step largely because drug products must be brought to a temperature above the cold pain threshold (CPT), or the temperature at which most people experience a cold sensation as painful, in order to decrease or eliminate cold-related pain during SC injection.

This exploratory study investigates the warming process of EMPAVELI during preparation and administration with the Empaveli Injector. The focus was on the enFuse® system by Enable Injections, used with EMPAVELI, to explore its capability to directly administer 20 mL of refrigerated EMPAVELI without on-counter warming, leveraging the drug's warming during preparation via conduction and body heat once applied to the patient. The main purpose of the study was to determine the extent to which the preparation of EMPAVELI with the enFuse, and the warming effect of body temperature during injection, could increase the temperature of the drug product. Additionally, the study aimed to assess whether these temperature increases result in the drug product reaching a temperature above the CPT, thereby avoiding cold-associated pain for patients and potentially eliminating the need for traditional on-counter warming.

Methods:

The preparation of EMPAVELI with the enFuse was carried out according to the manufacturer's instructions for use (IFU). To measure the warming of the drug product as it exits the enFuse and to simulate the thermal interactions of the device with the patient's body, an on-body thermal analog was developed. The on-body thermal analog was equipped with multiple thermocouple sensors, which measure temperature at various locations. Critically, it captures the temperature of the drug at the needle tip as it exits, providing an understanding of the drug temperature upon entering the patient in a real-life scenario.

Results:

EMPAVELI with a starting temperature of 5 ± 1°C, when transferred to the enFuse at an ambient temperature of 23 ± 1°C, exhibited an increase in immediate injection temperature of between 12.6 °C to 13.4 °C, predominantly influenced by transfer time. Body warming further elevated drug temperature by an additional 9.3 °C to 10.3 °C, dependent on the flow rate during dispensing. Notably, 100% of the measurements exceeded the median CPT of the general population, which is expected to be ≤ 10.1°C, without additional on-counter warming. The warming advantage seen with the enFuse was primarily attributed to the syringe's thermal mass, the duration between vial removal and the transfer process initiation, and heat generated from hand contact during drug withdrawal.

Conclusion:

These findings suggest that the enFuse system, combined with body heat during administration, effectively warms EMPAVELI to temperatures above the CPT, potentially eliminating the need for traditional on-counter warming and reducing the associated time delays for patients. The reduction or elimination of traditional on-counter warming may also enhance medication adherence in home settings by reducing preparation time. Handling inefficiencies and drug transfer to the device were minimized since the operators were highly familiar with the enFuse system. However, these factors are expected to contribute to an even greater warming benefit when performed by patients who are less familiar with the device due to longer preparation times. It is crucial to emphasize the exploratory nature of this study and to ensure that the preparation instructions on the EMPAVELI label are strictly followed regardless of these early findings.

Gunnerson:Enable Injections: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Harville:Enable Injections: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Waites:Enable Injections: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Desai:Enable Injections: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Rahman:Enable Injections: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.

For EMPAVELI, the first C3 complement inhibitor approved to treat Paroxysmal Nocturnal Hemoglobinuria (PNH), the standard protocol for preparation requires warming the vial for at least 30 minutes before injection. Our exploratory findings suggest that the enFuse system, combined with body heat during administration, effectively warms EMPAVELI to temperatures above the cold-pain threshold, potentially eliminating the need for traditional on-counter warming and reducing the associated time delays for patients.