KalVista Terminates KOMPLETE Trial of KVD824
High levels of liver enzymes cited as the reason
The Phase 2 KOMPLETE clinical trial testing the ability of oral KVD824 to prevent attacks in people with hereditary angioedema (HAE) has been terminated.
The decision by the therapy’s developer, KalVista Pharmaceuticals, was based on the observation of high levels of liver enzymes, a sign of inflammation or liver damage, in multiple patients in all treatment groups of the trial. There were no reports, however, of related symptoms, or higher levels of bilirubin, a marker of liver function.
“The health and safety of participants in our clinical trials is of utmost importance to us,” Andrew Crockett, KalVista’s CEO, said in a press release. “We made the difficult decision to terminate KOMPLETE because we concluded that the emerging safety profile of the current formulation will not meet our requirements for a best-in-class oral prophylactic [preventive] therapy.”
The company is still recruiting patients for its Phase 3 KONFIDENT trial (NCT05259917), which is assessing the therapeutic potential of sebetralstat (formerly known as KVD900) as a potential on-demand oral therapy for HAE attacks.
Because sebetralstat is a distinct compound from KVD824, no treatment-related liver enzyme changes have been seen in patients in any sebetralstat clinical studies, including KONFIDENT, according to KalVista. KONFIDENT data is anticipated in the second half of 2023.
KVD824 was designed to block the activity of kallikrein, an enzyme that is overactive in HAE. By suppressing kallikrein’s activity and the production of the pro-inflammatory molecule bradykinin, KVD824 was expected to reduce or prevent HAE swelling attacks.
The company launched KOMPLETE (NCT05055258) to evaluate KVD824 as a prophylactic HAE therapy. The trial was temporarily delayed by the U.S. Food and Drug Administration (FDA), which asked for more preclinical data and changes to the study’s protocol. Following a response from KalVista, the agency lifted the hold.
KOMPLETE enrolled 33 participants who were assigned randomly to one of three doses of KVD824 (300, 600, or 900 mg), or a placebo, given twice daily for 12 weeks (about three months). The study’s main goal was to assess the effect of treatment on the rate of HAE swelling attacks.
Seven participants experienced grade 3 (moderate-to-severe) or grade 4 (severe) elevations in liver enzymes, ranging from two to 12 weeks of treatment. These higher levels were seen across all of those treated with KVD824. One additional grade 4 elevation was observed in a patient before receiving the therapy.
The company stated it will assess the data for safety and efficacy to determine KVD824’s potential for any future development.
Meanwhile, KalVista is planning to move forward with sebetralstat’s clinical program and submit a new drug application (NDA) to the FDA in 2024 requesting its approval. The company also is advancing KV998086, an oral small molecule blocker of activated factor XII (FXIIa), to prevent HAE attacks. So far, KV998086 has shown promise in preclinical studies.
“This termination conserves our financial resources and allows us to focus on continuing to advance sebetralstat through the ongoing phase 3 program and towards a planned 2024 NDA filing,” Crockett said, “as well as on our emerging oral Factor XIIa inhibitor program as a potential once daily prophylactic therapy for people with HAE.”