KVD900-201
Research type
Research Study
Full title
A randomized, double-blind, placebo-controlled, phase II, cross-over clinical trial evaluating the efficacy and safety of KVD900, an oral plasma kallikrein inhibitor, in the on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema type I or II
IRAS ID
259690
Contact name
Sorena Kiani
Contact email
Sponsor organisation
KalVista Pharmaceuticals Ltd
Eudract number
2018-004489-32
Duration of Study in the UK
1 years, 6 months, 2 days
Research summary
Summary of Research
The study drug (KVD900) is being developed to treat hereditary angioedema (HAE) type I or type II.The study drug, KVD900, will be studied as a new oral treatment for HAE attacks. KVD900 is a plasma kallikrein inhibitor, meaning it works by attempting to slow down or stop the activity of the enzyme plasma kallikrein. An enzyme is a molecule that speeds up chemical reactions.
Plasma kallikrein is an important part of the body’s inflammatory response. This inflammatory response is part of our bodies self defence system which serves to protect us against infections and/or injury. Normally, plasma kallikrein circulates as an inactive enzyme thanks to protein C1-esterase inhibitor (C1INH). Uncontrolled activation of kallikrein, in the absence of its natural inhibitor C1INH, leads to excessive release of a substance called bradykinin that starts the swelling process (angioedema).
The test drug KVD900 is intended to control the activation of the enzyme (plasma kallikrein) reducing the amount of swelling and thus helping in the treatment of HAE.
This KVD900 has been tested in 68 subjects so far and has undergone comprehensive testing in what’s known as the pre-clinical stage of drug development. This includes testing in animals and testing in the laboratory.
This study will investigate how KVD900 will work in the human body; the study will measure the safety, pharmacokinetics (PK, how your body handles the drug), and how well the drug works.
The maximum duration of the study for the patient will be approximately 19 weeks.In this study KV900 (the drug) was shown to be statistically significant versus placebo in halting the progression of and symptomatically improving HAE (hereditary angioedema) attacks. The primary endpoint, all secondary endpoints and the key exploratory endpoints were all met. A single oral dose of KVD900 600 mg (6 × 100 mg tablets) was used to treat HAE attacks within 1 hour of start of attack. Eligible HAE attacks were mild or moderate at baseline and statistical analyses assessed both worsening and improving of the HAE attacks across multiple efficacy endpoints, all collected in real-time throughout the attack.
The primary efficacy endpoint showed a statistically significant difference in the time to conventional attack treatment within 12 hours between KVD900 and placebo. A lower proportion of subjects used conventional attack treatment within 12 hours of study drug in comparison to following treatment with placebo. Halting attack progression was also demonstrated by an increased time to use of conventional attack treatment, increased time to worsening on the Patient’s impression of severity (PGI-S) and a lower proportion of attacks that worsened on PGI-S over a 12-hour period following treatment with KVD900 versus placebo.
Following treatment with KVD900, subjects demonstrated significant improvement in HAE attacks in each subject reported outcome. A higher proportion of subjects had improvement by one level or more from baseline in PGI-S, complete HAE attack resolution defined as a severity rating of none on the PGI-S, HAE attack rated “a little better” or higher on Patient’s impression of change in severity (PGI-C) for 2 consecutive time points, HAE attack being rated “better” or higher on PGI-C and symptom relief following treatment with KVD900 versus placebo. The above efficacy results demonstrate a clear trend towards improvement in attacks as reported by the subjects. Complete HAE attack resolution was significantly shorter for KVD900 versus placebo.
The speed of efficacy described above may be attributed to the breakdown profile of KVD900 where KVD900 was rapidly absorbed following oral administration, with plasma levels of KVD900 quickly reaching maximum values with measurable concentrations detected within 0.25 hours. Subjects report rapid impressions of change as the most important indicator of a study drug’s efficacy, specifically that the attack is unlikely to get worse and has begun to resolve. The results from this study were consistent with data showing that early intervention in HAE attacks leads to improved subject outcomes versus placebo.
Early efficacy following treatment with KVD900 was also sustained over a 24-hour period. The efficacy outcomes at 12 and 24 hours were similar in all reported outcomes, despite KVD900 plasma concentrations being virtually eliminated from the plasma by 12 hours, demonstrating that a single dose of KVD900 was sufficient to treat HAE attacks with rapid initial efficacy and sustained outcomes through 24 hours. KVD900 was safe and well tolerated in HAE subjects and demonstrated a safety profile consistent with that observed in previous Phase 1 clinical studies. There was a low incidence of study drug-related adverse events (TEAE). The majority of TEAEs were experienced by 1 subject each. Overall, the most common TEAEs experienced by subjects were headache and nasopharyngitis.REC name
London - City & East Research Ethics Committee
REC reference
19/LO/0153
Date of REC Opinion
13 Mar 2019
REC opinion
Further Information Favourable Opinion