Endpoint definitions of vaso-occlusion pain events used in Phase 3 SCD clinical trials are varied, resulting in differing efficacy outcomes when using the same dataset. Our results support the conclusion that caution should be used when making comparisons between endpoints of different trials which assess the elimination or reduction of vaso-occlusive pain events.

Although we did identify some similarities in definitions of vaso-occlusion endpoints between SCD clinical trials, there were a number of key differences which have the potential to impact outcome assessments. The primary difference between trials was the length and frequency of medical care and whether narcotics were administered orally or IV during an acute pain event to meet an endpoint definition of vaso-occlusion. Although for all endpoints with the exception of exa-cel, patients had to have had an episode of acute pain for which there was no medically determined cause other than vaso-occlusion or sickling-related pain, and medical intervention was obtained by the patient, the broader definitions (exa-cel, crizanlizumab and L-glutamine, and voxelotor) required that a patient only need visit a medical facility and be treated for pain (oral or IV narcotics) to meet the endpoint, whereas the more restrictive definitions required the visit to the medical facility to be for a specific set duration of time (lovo-cel, reni-cel, and HU) and use of only IV narcotics to meet the endpoint definition (lovo-cel). Given that acute vaso-occlusive pain events associated with SCD often vary in intensity and duration, and that there are not necessarily any precipitating factors for these events [5], a broader definition is likely to be more inclusive of potential vaso-occlusive pain events than a more restrictive definition. However, it is clear from these comparisons that, to date, there has still not been a consistent definition of what constitutes an acute pain event due to vaso-occlusion applied across SCD clinical trials.

To understand the potential impact of different definitions of vaso-occlusion endpoints on trial outcomes, we assessed the same dataset using two different vaso-occlusion endpoints which represent broader and more restrictive definitions. Using the broad, inclusive criteria of severe VOC (exa-cel), there was one patient out of 30 who had severe VOCs following exa-cel infusion and did not meet the endpoint. The patient, who was reported to have a medical history of chronic pain from SCD, had several adjudicated severe VOCs following exa-cel infusion and therefore did not meet the primary endpoint of the study [14]. However, when the definition of severe VOE (lovo-cel) [8] was applied to this same dataset, all 30 patients were considered to be VOE-free, including the one patient who had adjudicated severe VOCs under the exa-cel definition. This example clearly demonstrates that the different definitions of vaso-occlusion used in endpoints in SCD clinical trials can lead to different presentations of clinical outcomes. It is also important to note that differences in definitions of vaso-occlusion were also applied to the inclusion criteria for the exa-cel and lovo-cel trials, and therefore may have also impacted the potential patient population entering either trial.

Beyond the analysis of endpoints in Phase 3 SCD clinical trials, several SCD therapies described here (lovo-cel, reni-cel, and exa-cel) have the potential to provide long-term, durable reductions and/or elimination of vaso-occlusive pain events. However, the differing definitions of vaso-occlusive and/or pain events will also make it challenging to contextualize long-term efficacy and to compare with allogeneic hematopoietic stem cell transplantation, which has traditionally been considered the only potentially curative therapy for eligible patients with SCD [15, 16]. Indeed, it could be argued that studies of allogenic transplantation are generally not designed or resourced to follow patients with this degree of specificity, and generally do not include an external monitoring body to adjudicate vaso-occlusive events. Further complexity comes from the existence of chronic pain syndromes in patients with SCD, which, while they may be the result of prior VOEs, may not be VOEs when experienced later, even after potentially curative therapy. One such example is joint pain resulting from avascular necrosis, where distinguishing between pain from avascular necrosis and VOE may be challenging and confound longer-term efficacy assessments.

There are some limitations which should be considered when interpreting results from this study. First, VOC endpoint definition comparisons were descriptive and were limited to the details provided at Clinical Trials.gov or in published literature. Second, the analysis of exa-cel data using the severe VOE definition was a post hoc analysis and was not pre-specified in the CLIMB SCD-121 trial protocol.