Patient feedback helps in design of Phase 3 trial of oral sebetralstat
Trial fully enrolled with 114 patients to test on-demand oral treatment
The design of an ongoing Phase 3 clinical trial testing sebetralstat as an on-demand oral treatment for swelling attacks in hereditary angioedema (HAE) was based on feedback from patients and data from a previous Phase 2 trial.
The approach was described in the study “Evaluation of patient-reported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat,” which was published in Clinical and Translational Allergy. The work was funded by sebetralstat’s developer, KalVista Pharmaceuticals.
HAE is characterized by attacks of sudden swelling, which can be life-threatening in some cases. When an attack occurs, it’s recommended that patients receive prompt on-demand treatment to resolve the swelling.
Several on-demand treatments for HAE attacks are available, but all of them are administered via injection, given under the skin or into the vein. This “adds complexity to patient decision-making and may contribute to undertreatment or delays in treatment,” the researchers wrote.
HAE treatment delays are common
Real-world data has shown that treatment delays are common. These may be associated with several factors, including the time needed to obtain and prepare the medication, the need to find an appropriate and hygienic location to administer it, and hesitation related to anticipated pain or other side effects.
KalVista is developing sebetralstat to be the first oral on-demand treatment for HAE, which may help with adherence and possibly enable patients “to treat attacks as early as possible, increasing the likelihood of rapid symptom relief and minimizing attack duration and severity,” the researchers wrote.
The experimental treatment works by blocking the activity of kallikrein, the enzyme responsible for producing bradykinin, the signaling molecule whose overproduction triggers swelling in HAE.
Data from a previous Phase 2 trial (NCT04208412), which involved 68 adults with HAE, indicated that on-demand treatment with sebetralstat was generally safe and faster than a placebo at halting and resolving swelling attacks. Findings favoring the investigational therapy were seen across multiple outcome measures.
Following these promising results, KalVista set out to conduct a global Phase 3 trial, dubbed KONFIDENT (NCT05259917), to confirm the therapy’s safety and efficacy in a larger number of patients. The goal was to use the study’s data, should they be positive, to support an application seeking sebetralstat’s approval.
In designing the Phase 3 study, one of the biggest questions that needed to be addressed was what the primary goal should be. It’s critical that the main goal lines up with patients’ actual experiences of the disease and symptoms.
As such, KalVista and an international team of researchers surveyed seven people with HAE (ages 18-74 years; all from the U.S.), asking their opinions on the different patient-reported tools that were used to track outcomes in the earlier Phase 2 study.
71% favored Patient Global Impression of Change measure
While the patients thought all the evaluated tools could provide meaningful results, 71% of them favored the Patient Global Impression of Change, or PGI-C, “because they felt that the PGI-C scale increments most appropriately reflected the gradual change experienced by most patients when treating an HAE attack,” the team wrote.
The PGI-C is a subjective measure that asks a patient to rate how their symptoms have changed since treatment, with seven possible options: “much better,” “better,” “a little better,” “no change,” “a little worse,” “worse,” or “much worse.”
Again, 71% of the patients said a change of at least “a little better” best represented a meaningful improvement in attack symptoms following on-demand treatment.
Statistical analysis on the Phase 2 data indicated patients who had reported feeling at least “a little better” on the PGI-C at two consecutive time points were also very likely to report improvements on other measures.
Also, most patients who reported feeling “a little better” at two time points in a row within four hours after treatment then went on to report feeling “better” at later time points.
“The PGI-C rating of at least ‘A Little Better’ for two time points in a row is a clinically meaningful, patient-preferred efficacy outcome measure to detect the earliest signs of symptom relief following on-demand treatment for HAE attacks and is predictive of other efficacy measures, including attack resolution,” the researchers wrote.
Based on these data, time to beginning of symptom relief, defined as the PGI-C rating of at least “a little better” for two consecutive time points within 12 hours of treatment, was selected as the Phase 3 trial’s main goal.
Other measures used in the Phase 2 trial are also included in the Phase 3 study as secondary goals. In addition, the General Anxiety-Numeric Rating Scale will be used as an exploratory goal to evaluate changes in anxiety during treatment of HAE attacks.
“KONFIDENT is the first on-demand study using the General Anxiety-Numeric Rating Scale,” the researchers wrote, adding that understanding the anxiety associated with swelling attacks and its changes with treatment may help contribute to overall patient well-being.
Phase 3 trial includes younger patients
The trial will include HAE patients, 12 and older, who have experienced at least two HAE attacks in the three months prior while being on a stable dose and regimen of preventive or on-demand treatment.
“These criteria expand the eligible patient population compared with the earlier phase 2 trial, which was limited to adults who were not on [preventive treatment],” the researchers wrote.
During the trial, three separate swelling attacks will be assessed in each participant. In random order, attacks will be treated with a 300 mg oral tablet, a 600 mg sebetralstat tablet, and a placebo tablet.
The scientists then conducted mathematical tests to calculate how many trial participants would be needed to detect a statistically meaningful effect.
The analyses estimated that, if sebetralstat is effective as expected, a total of 84 patients each treated for three HAE attacks would provide at least 90% power to detect statistically meaningful differences between the treatment and a placebo in the main goal.
Accounting for patients who won’t complete treatment of three attacks, the target enrollment was about 114 patients, which was reached a few months ago. Patients were recruited at sites across North America, Europe, and Asia-Pacific countries.
Results from the trial are expected by the end of this year.