This morning, Diurnal highlighted the publication in a peer reviewed journal of the completed Chronocort Phase 3 trial in CAH (Congenital Adrenal Hyperplasia) patients along with the extension study.
With the primary endpoint of the Phase 3 study at 24 weeks and the 18 month extension study ( in patients who chose to continue on Chronocort), this represents a significant body of safety data, supporting the use of a modified release preparation of hydrocortisone like Chronocort in this needy patient population.
The publication also provides further detail on the data supporting the use of Chronocort, and the importance of circadian delivery to optimise treatment in these patients. As we have previously highlighted, the treatment of CAH requires a balance between lowering the high levels of overnight male hormones (androgens) and minimising the risk of too much glucocorticoid (hydrocortisone). High levels of androgens can result in issues such as poor fertility and precocious puberty, and insufficient glucocorticoid increases the risk of, sometimes life-threatening, adrenal crisis.
While acknowledging the missed primary endpoint, the publication confirms the benefits seen with Chronocort in a post hoc (follow-up) analysis of the Phase 3 study. Clinically relevant improvement in hormonal control was achieved with Chronocort than standard glucocorticoid as seen by a greater reduction in relevant biochemical markers (usually 17OHP) from the start of the study to both week 4 and week 24. Importantly, a statistically significant improvement was observed in hormonal control during the important early morning/afternoon (7am-3pm) while other measures (Area Under the Curve) also confirmed the positive impact of Chronocort over standard glucocorticoid therapy. In the extension part of the study, after prolonged treatment, 80% of patients experienced good disease control (measured by 17OHP) compared with 52% at the beginning of the Phase 3 study. Other positive observations included the restarting of menstruation and improved fertility in patients receiving Chronocort.
One of the key issues for patients is to minimise the impact of excess glucocorticoid therapy. The data is sufficiently reassuring to suggest that most patients can be controlled with a normal replacement dose of Chronocort compared to supraphysiological glucocorticoid doses (doses exceeding that normally found in healthy individuals) currently used to treat CAH patients. This is important since reducing the glucocorticoid dose is a central tenet of new potential approaches in CAH.
From a safety perspective, it is reassuring that hydrocortisone (the active ingredient in Chronocort) is a well characterised treatment. The absence of adrenal crises during the controlled (Phase 3) study in patients receiving Chronocort is highly reassuring, and while there were several observed during the extension study, we note that this is not out of kilter with historical rates.
Overall, the data highlighted in the publication confirms the earlier data shared by Diurnal, but with data and detail to support previous conclusions. If Chronocort is approved by the EMA during Q1 2021, the data suggests that it potentially offers a satisfactory solution for many CAH patients, and should represent a powerful addition to the physicians armamentarium in treating this needy patient population.