KalVista asks FDA to approve oral, on-demand sebetralstat for HAE

KalVista plans similar applications to regulatory agencies in UK, EU, Japan

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by Steve Bryson, PhD |

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KalVista Pharmaceuticals has submitted an application to the U.S. Food and Drug Administration (FDA) requesting the approval of sebetralstat, an oral on-demand treatment for people, 12 and older, with hereditary angioedema (HAE).

The agency now has 60 days to determine whether the application, submitted in the form of a new drug application, or NDA, is complete and acceptable for review. A decision on the status of the submission is expected in September.

KalVista also plans to submit similar applications to regulatory agencies in the U.K., the European Union, and Japan.

“This NDA submission represents a pivotal moment not only for our company, but for the entire HAE community as we seek to bring an important therapeutic advancement through the first-ever, oral on-demand treatment for HAE,” Ben Palleiko, CEO of KalVista, said in a company press release.

“If approved, we believe sebetralstat could become a foundational treatment that will transform the way people living with HAE treat their disease,” Palleiko said.

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On-demand sebetralstat quickly eases attacks in long-term HAE trial

Sebetralstat blocks activity of enzyme called kallikrein

Sebetralstat, formerly called KVD900, is designed to block the activity of an enzyme called kallikrein. Too much kallikrein activity leads to the excessive production of bradykinin, a molecule that drives HAE swelling attacks. By blocking kallikrein activity at the onset of swelling, the therapy works to lower bradykinin production, helping to resolve the attack.

Data from the Phase 3 KONFIDENT trial (NCT05259917) and the KONFIDENT-S extension study (NCT05505916) supported the application.

KONFIDENT enrolled 136 people, 12 years and older, with HAE. Each participant received on-demand treatment for three swelling attacks: either 300 or 600 mg of sebetralstat, or a placebo, given in random order. For each attack, patients could take the therapy twice if needed.

Meeting all of its goals, KONFIDENT demonstrated that both doses of sebetralstat provided rapid symptom relief and resolution compared with the placebo, according to top-line data. At the lower dose, the median time to the beginning of symptom relief was 1.61 hours, and at the higher dose, it was 1.79 hours. Symptom relief occurred at a median of 6.72 hours with a placebo.

If approved, we believe sebetralstat could become a foundational treatment that will transform the way people living with HAE treat their disease.

Moreover, a single dose of the therapy, not the two allowed in the trial, was sufficient to lessen or completely resolve most swelling attacks.

After completing KONFIDENT, participants could enroll in the long-term KONFIDENT-S extension study, where all would receive on-demand treatment with sebetralstat for swelling attacks. KONFIDENT-S is still actively enrolling HAE patients at clinical sites worldwide.

Interim findings from KONFIDENT-S showed most HAE patients who took sebetralstat within 10 minutes of the start of a swelling attack began to experience symptom relief within two hours, with complete resolution occurring within about a day.

If approved, sebetralstat would be the first oral, on-demand therapy for HAE patients, including those ages 12-17. KalVista believes the treatment will fill an unmet need in this patient age group due to the challenges associated with injectable medications.

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KalVista will seek global approvals of sebetralstat for HAE this year

KalVista plans KONFIDENT-KID trial to test sebetralstat in younger patients

The company is also planning to launch a trial testing sebetralstat in younger patients, called KONFIDENT-KID, later this year. If results from this study are positive, they may enable the extension of the therapy’s indication to patients ages 2-11.

“This [NDA submission] is the culmination of the entire KalVista team’s long-term efforts, with the critical support of people living with HAE,” Palleiko said.

“Our partnerships with the HAE scientific community, the [U.S. Hereditary Angioedema Association] and [HAE International] patient advocacy organizations, regulators and other stakeholders … demonstrate our commitment to addressing persistent unmet needs for people living with this rare disease,” Palleiko added.

Meanwhile, the company is planning to test orally disintegrating tablets (ODT) of sebetralstat, which dissolve directly in the mouth, in HAE patients. This formulation is for those who find it difficult to swallow film-coated tablets, particularly during a swelling attack affecting the face, neck, or throat.

In KONFIDENT-S, participants have been receiving on-demand treatment with 600 mg of sebetralstat, given as two film-coated tablets during an attack. KalVista plans to switch to the ODT formulation by the end of the year, to support a future application seeking the approval of this alternative formulation.

Additional data from KONFIDENT and KONFIDENT-S will be presented at the upcoming 2024 Annual Scientific Conference of the American College of Allergy, Asthma, and Immunology, which will be held in Boston, Massachusetts, in October.