Exposure-Response Analysis of Donidalorsen for the Treatment of Hereditary Angioedema

Abstract

Hereditary angioedema (HAE) is characterized by recurrent attacks of severe tissue swelling. In the OASIS-HAE phase 3 study (NCT05139810), donidalorsen, an RNA-targeted antisense oligonucleotide that reduces prekallikrein production in the liver, significantly reduced HAE attack rates. To characterize the relationship between prekallikrein concentrations and HAE attack rates following donidalorsen and predict the efficacy of potential dosing regimens, an exposure-response model was developed using data from OASIS-HAE. Simulations were conducted to evaluate the following regimens: 80 mg once every 4 weeks (Q4W), 8 weeks (Q8W), 1 month (Q1M), and 2 months (Q2M), and a switch to Q2M dosing for patients who were attack-free for 3 months on the Q1M regimen. The relationship between prekallikrein concentrations and HAE attack rates was well characterized by a sigmoidal E_max (maximum effect) model with baseline attack rate and baseline prekallikrein concentration included as covariates. The average prekallikrein concentration estimated to result in a 90% reduction in attack rate (EC₁₀) was 47.1 mg/L. Predicted percent reductions in attack rates at steady state were similar for Q4W (84.1%) vs. Q1M (82.9%) and Q8W (72.6%) vs. Q2M (70.2%) dosing. Predicted reductions in attack rate remained similar and clinically meaningful in patients who switched from Q1M to Q2M dosing (94.0% in month 1 and 91.3% in month 2 of the 2-month dosing interval at steady state). Overall, exposure-response analyses supported the efficacy of Q1M and Q2M dosing and indicated that switching to Q2M dosing could be a viable approach for patients who are attack-free on the Q1M regimen.

Keywords: exposure–response; modeling; pharmacodynamics; pharmacokinetics; pharmacokinetics–pharmacodynamics.

FIGURE 1

Relationship between HAE attack rates and predicted prekallikrein concentrations. (a) The solid line represents the model‐predicted relationship between 4‐week normalized HAE attack rate and predicted prekallikrein concentrations for a typical patient with a baseline concentration of 132 mg/L and baseline per‐4‐week normalized HAE attack rate of 3.47. The gray area represents the 90% prediction interval of the predicted relationship. The red and blue dots represent the observed mean per‐4‐week normalized HAE attack rates and time‐matched predicted per‐4‐week average prekallikrein concentrations for the patients in the Q4W and Q8W dosing regimens at baseline and in each 4‐week period of OASIS‐HAE. (b) Corresponding plot for change from baseline in per‐4‐week normalized HAE attack rate vs. time‐matched change from baseline in predicted per‐4‐week average prekallikrein concentration for the typical patient (solid line) and for each 4‐week period of OASIS‐HAE (dots). The dots at the origin (0,0) represent baseline. CFB, change from baseline; HAE, hereditary angioedema; PKK, prekallikrein; Q4W, once every 4 weeks; Q8W, once every 8 weeks.

FIGURE 2

Goodness of fit and external validation of the exposure–response model. (a) Comparison of the observed per‐4‐week normalized HAE attack rate in OASIS‐HAE and the model population‐predicted per‐4‐week normalized HAE attack rate. (b) Comparison of the observed per‐4‐week normalized HAE attack rate in OASIS‐HAE and the model individual‐predicted per‐4‐week normalized HAE attack rate. (c) Comparison of the observed per‐4‐week normalized HAE attack rate and the model‐predicted per‐4‐week normalized HAE attack rate in the phase 2 donidalorsen clinical study. Black dots are individual data points. The black dashed line is the identity line. The red line is a LOESS regression line in (a) and (b) and a linear regression line in (c). HAE, hereditary angioedema; LOESS, locally estimated scatterplot smoothing.

FIGURE 3

Representative individual plots of predicted and observed per‐4‐week HAE attack rate vs. study week in the OASIS‐HAE study. Representative individual plots of predicted and observed per‐4‐week HAE attack rates vs. study week for patients in the (a) Q4W and (b) Q8W dosing groups. Observed per‐4‐week normalized HAE attack rates are represented by the black dots. The green and blue solid lines represent the population‐predicted and individual‐predicted per‐4‐week normalized HAE attack rates, respectively. BL, baseline; HAE, hereditary angioedema; Q4W, once every 4 weeks; Q8W, once every 8 weeks.

FIGURE 4

Simulated HAE attack rate profiles by dosing regimen. Simulated per‐4‐week normalized HAE attack rates over time for (a) Q4W and Q1M dosing and (b) Q8W and Q2M dosing. The dots represent the median, and the error bars represent the 10th and 90th percentiles. HAE, hereditary angioedema; Q1M, once every month; Q2M, once every 2 months; Q4W, once every 4 weeks; Q8W, once every 8 weeks.

FIGURE 5

Predicted prekallikrein concentrations over time in simulated patients who switched dosing regimens from Q1M to Q2M. The dots represent the median, and the error bars represent the 10th and 90th percentiles. PKK, prekallikrein; Q1M, once every month; Q2M, once every 2 months.

FIGURE 6

Simulated per‐4‐week HAE attack rate profiles for switching dosing regimens from Q1M to Q2M. The dots represent the median, and the error bars represent the 10th and 90th percentiles. HAE, hereditary angioedema; Q1M, once every month; Q2M, once every 2 months.