PMID- 35086692
OWN - NLM
STAT- MEDLINE
DCOM- 20220608
LR  - 20220719
IS  - 1097-6825 (Electronic)
IS  - 0091-6749 (Linking)
VI  - 149
IP  - 6
DP  - 2022 Jun
TI  - KVD900, an oral on-demand treatment for hereditary angioedema: Phase 1 study 
      results.
PG  - 2034-2042
LID - S0091-6749(21)02666-X [pii]
LID - 10.1016/j.jaci.2021.10.038 [doi]
AB  - BACKGROUND: Attacks of hereditary angioedema are attributed to excessive plasma 
      kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to 
      generate the proinflammatory hormone bradykinin. OBJECTIVE: We evaluated the 
      safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, 
      an orally administered inhibitor of PKa in healthy adults. METHODS: KVD900 was 
      administered in 2 clinical studies. In the first study, healthy adult men 
      received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 
      100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg 
      doses of KVD900 (6 x 100 mg tablets) under fed and fasting conditions 
      (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg 
      of KVD900 tablets at 8-, 4-, and 2-hour intervals. RESULTS: Overall, 98 healthy 
      participants received KVD900. All adverse events (AEs) were mild, except for a 
      single moderate AE (headache). Exposure to KVD900 was proportional to dose. The 
      PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean 
      (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, 
      mean (coefficient of variation) area under the curve (AUC(0-24)) of 18,600 
      (22.5) h⋅ng/mL, and median (range) time to maximum plasma concentration of 0.5 
      (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 
      minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours 
      after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg 
      dose was attained within 20 minutes and maintained for 8 to 10 hours. CONCLUSION: 
      These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 
      rapidly achieves near-complete PKa inhibition and is generally safe and well 
      tolerated. GOV IDENTIFIER: NCT04349800.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Maetzel, Andreas
AU  - Maetzel A
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass; Institute of Health 
      Policy, Management & Evaluation, University of Toronto, Toronto, Ontario, Canada.
FAU - Smith, Michael D
AU  - Smith MD
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - Duckworth, Edward J
AU  - Duckworth EJ
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - Hampton, Sally L
AU  - Hampton SL
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - De Donatis, Gian Marco
AU  - De Donatis GM
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - Murugesan, Nivetha
AU  - Murugesan N
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - Rushbrooke, Louise J
AU  - Rushbrooke LJ
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - Li, Lily
AU  - Li L
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
FAU - Francombe, Danielle
AU  - Francombe D
AD  - Simbec-Orion Ltd, Merthyr Tydfil, United Kingdom.
FAU - Feener, Edward P
AU  - Feener EP
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass. Electronic address: 
      epf@kalvista.com.
FAU - Yea, Christopher M
AU  - Yea CM
AD  - KalVista Pharmaceuticals, Salisbury and Cambridge, Mass.
LA  - eng
SI  - ClinicalTrials.gov/NCT04349800
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220124
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - 0 (Kininogen, High-Molecular-Weight)
RN  - 0 (Tablets)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - *Angioedemas, Hereditary/drug therapy
MH  - Area Under Curve
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Healthy Volunteers
MH  - Humans
MH  - Kininogen, High-Molecular-Weight
MH  - Male
MH  - Tablets
OTO - NOTNLM
OT  - Hereditary angioedema
OT  - clinical trial
OT  - plasma kallikrein
EDAT- 2022/01/29 06:00
MHDA- 2022/06/09 06:00
CRDT- 2022/01/28 05:36
PHST- 2021/05/21 00:00 [received]
PHST- 2021/09/30 00:00 [revised]
PHST- 2021/10/27 00:00 [accepted]
PHST- 2022/01/29 06:00 [pubmed]
PHST- 2022/06/09 06:00 [medline]
PHST- 2022/01/28 05:36 [entrez]
AID - S0091-6749(21)02666-X [pii]
AID - 10.1016/j.jaci.2021.10.038 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 2022 Jun;149(6):2034-2042. doi: 
      10.1016/j.jaci.2021.10.038. Epub 2022 Jan 24.