Discussion
autistic, weakness
RECRUITMENT
Overall SB-121 use was well tolerated and safe in 15 adolescents and adults with ASD. Treatment compliance in this pilot study was excellent which indicated that, given a standardized approach to reconstituting the formulation, patients would be able to take it as instructed. The enrolled participant sample was well representative of males with ASD broadly marked by variation in cognitive skills and severity of core ASD symptoms at baseline. Clinically, we documented clear directional improvements in adaptive behavior as measured by Vineland-3, which warrants replication in larger-scale study. Given the broad inclusion criteria for ASD utilized in this first-in-humans study, the Vineland-3 results are of particular interest as adaptive behavior deficits would be broadly expected in participants with ASD and this may have enabled this outcome measure to detect change in the context of significant baseline sample phenotypic heterogeneity. Additionally, the use of broader inclusion criteria in this study has allowed us to observe differences in response to SB-121, as some participants responded more robustly to treatment than others. Studying a diverse group of participants with ASD may help identify the subpopulations that respond more readily to treatment.The Vineland-3 findings are in contrast to behavioral findings from the ABC where no trends in SB-121-associated change were noted. This may be due to a lack of impact of SB-121 on interfering behaviors in ASD, but also may be due to significant likely floor effects with use of the ABC in this specific sample of autistic individuals who had very low ABC scores at baseline. Broad interpretation of ABC score change in ASD trials is difficult in cases where inclusion criteria do not pre-specify ABC subscale or even an ABC total threshold score for study inclusion. It is possible that an early phase ASD clinical trial recruitment may bias towards enrollment of participants without significant interfering behavior that could preclude active study participation over a series of in person trial visits.Although treatment-associated directional improvement was noted on the Vineland-3, this improvement was not simultaneously captured by clinician CGI-I ratings. The CGI-I is a clinician-rated global measure that takes into account all information available including interview with subject and primary caregiver; however, in the current study, daily functional skills were not specifically asked about and thus would not have been incorporated into the CGI-I rating unless the primary caregiver shared this information with the clinician. In addition, the CGI-I may be more prone to placebo effect especially in the context of a small first-in-disorder trial since reporting may tend to more uniformly positive than detailed, item by item, report. Last, it is also possible that the potential disconnect between VABS-3 improvement and CGI-I rating is a product of small sample size statistical modeling.The finding that SB-121 was associated with a trend towards increased preference for viewing social versus non-social stimuli represents a quantitative, performance-based confirmation that this treatment could potentially enhance social interest in autistic individuals. Importantly, this was a trending quantitative correlate to improved adaptive behavior noted with treatment suggesting improved adaptive behavior as rated by a parent-rated measure may generalize to more real-world performance, especially within social interest. Thus, our findings warrant a larger-scale study for replication and extension.Additional limitations of this report include a very small sample size that limited any ability to phenotypically define the subgroup of participants who appear to drive the overall positive directional findings of Vineland-3, ABC score, and social viewing as measured by eye tracking. To address this potential disconnect between CGI-I and VABS-3 ratings, in future study consideration to including prompts to evaluate daily functioning more thoroughly during the clinical CGI-I evaluation may be warranted. Further, since females were not represented in this study this omission is a study weakness and is likely a result of a small sample size and not stratifying enrollment by sex assigned at birth. Given the Phase I nature of the pilot study, had the sample included female participants, we would have not had any power to detect potential sex-associated differences in SB-121 tolerability or clinical response. Despite the gastrointestinal focus of the SB-121 intervention, we lack detailed assessment of GI symptoms in this trial, including potential quantitative change of stool features following SB-121 treatment. In future work it will be important to quantitatively evaluate GI symptoms at baseline and following treatment including potential use of quantitative evaluation of stool sampling given SB-121 direct exposure is limited to the gastrointestinal lumen. While a positive trend for plasma oxytocin measurements was observed when participants were taking SB-121, we note that there are significant limitations to plasma oxytocin measurements. Oxytocin is a notoriously difficult hormone to assay due to having a short half-life, being poorly immunogenic, and its tendency to bind to molecules in plasmaThis Phase Ib study report on the first-in-humans use of SB-121 in male autistic participants provides data supporting future larger placebo-controlled studies of this compound in this autistic patients. The findings of a favorable safety profile of SB-121 in this sample of 15 individuals combined with significant improvements in Adaptive Behavior with treatment that is further corroborated by performance-based positive change in social engagement, indicates this treatment may be of benefit in ASD. It will be important in larger-scale studies to make efforts to rigorously phenotype the medical and gastrointestinal profile of participants in addition to classic clinical descriptions of behavior and cognition to potential define a subgroup who may best respond to treatment. This is of particular importance given the potential strong subgroup response we noted even in this small-scale study that appeared to drive overall positive clinical change.