Pharvaris N : Unmanned (CIIC Spring 2026) XR and IR e poster&slides 31Mar2026 FINAL UPLOAD noQR

Published: 2026-04-16 17:22:18 ET PHVS

Published on 04/16/2026 at 05:22 pm EDT

Evaluating Safety Margins of the Use of Deucrictibant Extended-Release Tablet in Combination with Deucrictibant Immediate-Release Capsule

Anne Lesage1, Juan Bravo2, Zhi-Yi Zhang3, Monica Rodriguez4, Peng Lu3, Nieves Crespo2

1GrayMatters Consulting, Schilde, Belgium; 2Pharvaris GmbH, Zug, Switzerland; 3Pharvaris Inc., Lexington, MA, USA; 4CTI Facts, Bilbao, Spain

Objective

To derive human exposures across the anticipated dosing scenarios involving once-daily XR tablet combined with one or two IR capsules and characterize corresponding safety margins based on available nonclinical and clinical data.

Deucrictibant 50 mg BID

XR + 1 IR

XR + 1 IR + 1 IR

XR + 1 IR

XR + 1 IR + 1 IR

Cmax (ng/mL)

693

281

327

2.5

2.1

AUC0-24h (ng·h/mL)

9716b

1923

2683

5.1

3.6

References

14. Aygören-Pürsün E, et al. Lancet Haem. 2026; DOI: 10.1016/S2352-3026(26)00004-9. 15. CHAPTER-3.

https://clinicaltrials.gov/study/NCT06669754. Accessed March 12, 2026. 16. CHAPTER-4. https://clinicaltrials.gov/study/NCT06679881. Accessed March 12, 2026. 17. Aygören-Pürsün, et al. Presented at: EAACI; May 31-June 3, 2024; Valencia, Spain. 18. CREAATE. https://clinicaltrials.gov/study/NCT07266805. Accessed March 12, 2026.

XR + 1 IRa

281

1923

XR + 1 IR + 1 IRa

327

2683

1xIR 2xIR 3xIR 4xIR

1xIR 2xIR 3xIR 2h inter 4xIR 2h inter

EC85, 85% effective concentration; IR, immediate-release; XR, extended-release. Error bars represent 90% confidence interval. aSingle oral dose of 40 mg XR tablet or two doses of 20 mg

deucrictibant IR capsule. bOne or two doses of IR capsules on top of XR tablet at steady state.

Time (hours)

250

200

150

100

XR + 1 IR (60 mgb)

XR + 2 IR (80 mgb) EC85

450

400

350

300

Time (hours)

350

300

250

200

150

100

XR (40 mga)

IR (2 x 20 mga) EC85

Figure 1. Linear plasma concentration-time profiles

450

400

Results

Deucrictibant XR tablet is formulated for prophylaxis and maintains plasma concentrations above the effective concentration estimated to provide 85% of the maximal response (EC85; 13.8 ng/mL) for >24 hours. Deucrictibant IR capsule is formulated for on-demand treatment and rapidly exceeds EC85 (Figure 1A).

Plasma concentration-time profiles for evaluated combined use scenarios are presented in

Figure 1B.

In the scenario where 1 IR capsule is taken in addition to 1 XR tablet (XR + 1 IR):

The anticipated human Cmax (281 ng/mL) would result in a margin of 8.9- to 19-fold the nonclinical Cmax at the NOAEL in different species (Table 2, Figure 2A).

The total area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24h) in humans is estimated at 1923 ng·h/mL with a margin of 2.8- to 11-fold the AUC0-24h at the nonclinical NOAEL in different species (Table 3, Figure 2B).

In the scenario where a second IR capsule is administered 4 hours after the first IR capsule in addition to 1 XR tablet (XR + 2 IR):

The margin for the estimated human Cmax of 327 ng/mL is maintained between 7.7- and 16-fold the nonclinical Cmax at the NOAEL in different species (Table 2, Figure 2A).

The human AUC0-24h is estimated to be 2683 ng·h/mL with a margin of 2- to 7.9-fold the AUC at the NOAEL in different species (Table 3, Figure 2B).

Remains below the highest dose

explored in human trials (100 mg, without adverse reactions)

20 mg

AUC0-24, area under the plasma concentration-time curve from time zero to 24 hours; Cmax, peak plasma concentration; h, hours; IR, immediate-release; NOAEL, no observed adverse-effect level; XR, extended-release. Images not a direct representation of the deucrictibant XR tablet or IR capsule.

20 mg

AUC0-24h

20 mg

XR 40 mg ≥2.0-fold

20 mg

Cmax

≥7.7-fold

40 mg

20 mg

≥2.8-fold

40 mg

≥8.tı-fold

40 mg

The combined use of deucrictibant extended-release (XR) 40 mg tablet and immediate-release (IR) 20 mg capsule(s) in the event of an attack occurring during prophylactic treatment with XR tablet is supported by adequate safety margins, subject to approval of each formulation by regulatory authorities.

Systemic exposure Safety margins

Key tafieaways

Bacfiground

Bradyfiinin-mediated angioedema (AE-BK): includes hereditary angioedema (HAE) with C1 inhibitor deficiency (HAE-C1INH) or with normal levels of C1 inhibitor (HAE-nC1INH) and acquired angioedema due to C1 inhibitor deficiency (AAE-C1INH).1-5 AE-BK is characterized by painful and often disabling swelling attacks.1-5

Deucrictibant: an investigational, selective, orally administered bradykinin B2 receptor antagonist under development for prophylactic (extended-release [XR] tablet) and on-demand

(immediate-release [IR] capsule) treatment of AE-BK attacks.6-18

Combined use: of deucrictibant XR tablet and deucrictibant IR capsule may occur in the

real-world setting, subject to regulatory approval of each formulation, if deucrictibant IR capsule is used in the event of an attack occurring during prophylactic treatment with XR tablet.

Methods

Safety margins for the combined scenarios were calculated using human exposure simulations performed with a population pharmacokinetic model combining XR and IR administration, clinical exposure at the highest dose tested (50 mg twice daily [BID]), and animal systemic exposure at the no observed adverse-effect level (NOAEL) in toxicity studies in different species.

The evaluated scenarios (Table 1) included daily-dose deucrictibant XR tablet (40 mg, at steady state) combined with one deucrictibant IR capsule (20 mg), or two deucrictibant IR capsules taken 4 hours apart.

- Scenarios assumed that the first IR capsule was taken by 6 hours after the XR tablet, such that the peak plasma concentrations (Cmax) for the XR tablet and IR capsule would be reached at the same time, providing a maximum peak of exposure.

A post-hoc analysis of CHAPTER-113,14 assessed mean duration of breakthrough attacks, in placebo and deucrictibant groups, that were treated with a single dose of icatibant, another bradykinin B2 receptor antagonist, for on-demand treatment of attacks.

Table 1. Estimated systemic concentrations for combined prophylactic and on-demand treatment of AE-BK in humans

Total dose Total Cmax Total AUC0-24h

(mg) (ng/mL) (ng·h/mL)

AE-BK, bradykinin-mediated angioedema; AUC0-24h, area under the plasma concentration-time curve from time zero to 24 hours; Cmax, peak plasma concentration; h, hours; IR, immediate-release; Tmax, time to peak maximum concentration; XR, extended-release. aFor the combined use of XR and IR it is assumed that the first IR dose is taken at the time where both Tmax values are expected to coincide, providing a maximum peak of exposure.

14000

12000

10000

AUC, area under plasma concentration-time curve; BID, twice daily; Cmax, maximum plasma concentration; EC85, 85% effective concentration; IR, immediate-release; Max, maximum; NOAEL, no observed adverse effect level; XR, extended-release. aImages not a direct representation of the deucrictibant XR tablet or IR capsule.

XR + 2 IR

XR + 1 IR

2 IR

1 XR

6000

4000

2000

7.9x

11x

13x

8000 18x

Max human AUC0-24h (50 mg BID)

Max nonclinical NOAEL

Monfiey NOAEL

16000

1 XR 2 IR XR + 1 IR XR + 2 IR

EC85(13.8 ng/mL)

1500

1000

500

14x

16x

17x

2000 59x

Figure 2. Safety margins for (A) Cmax- and (B) AUC-related effectsa

4000 Max nonclinical NOAEL

3500

3000

2500

Results

Table 2. Safety margins to the nonclinical Cmax at the NOAEL in different species for combined prophylactic and on-demand treatment of AE-BK

2 IRa

XR + 1 IRb

XR + 1 IR + 1 IR

after 4hb

AE-BK, bradykinin-mediated angioedema; Cmax, maximum plasma concentration; h, hours; IR, immediate-release; NOAEL, no observed adverse effect level; Tmax, time to maximum concentration; XR, extended-release. aTwo deucrictibant IR capsules taken 4 hours apart. bFor the combined use of XR and IR it is assumed that the first IR dose is taken at the time where both Tmax values are expected to coincide, providing a maximum peak of exposure. cThe estimated systemic mean exposures in humans based on population pharmacokinetics modeling.

Max human Cmax (50 mg BID)

Monfiey NOAEL

Results

Table 3. Safety margins to the nonclinical AUC at the NOAEL in different species for combined prophylactic and on-demand treatment of AE-BK, as unbound concentration

2 IRa

XR + 1 IRb

XR + 1 IR + 1 IRb

AE-BK, bradykinin-mediated angioedema; AUC, area under the plasma concentration-time curve from time zero to 24 hours or the last measured concentration; IR, immediate-release; NOAEL,

no observed adverse effect level; popPK, population pharmacokinetics; Tmax, time to maximum plasma concentration; XR, extended-release. aTwo deucrictibant IR capsules taken 4 hours apart. bFor the combined use of XR and IR, it is assumed the first IR dose is taken at the time where both Tmax values are expected to coincide, providing a maximum peak of exposure. cThe estimated systemic mean exposures in humans based on popPK modeling. dNo evidence of sex-related differences in toxicologic response was identified, therefore only the sex with higher exposure is presented.

In both combined scenarios, the estimated systemic exposure remains below the highest exposure explored in humans following clinical administration of deucrictibant 100 mg (as

50 mg BID) (Table 4, Figure 2A and B), a dose that was not associated with adverse reactions.

Table 4. Exposure coverage of potential administration of deucrictibant XR tablet with IR capsule by highest dose tested in humans (50 mg BID)

Exposure

Clinical study

Combination of deucrictibant XR with IRa

Safety margina

AUC0-24h, area under the plasma concentration-time curve from 0 to 24 hours; BID, twice daily; Cmax, peak plasma concentration; h, hours; IR, immediate-release; Tmax, time to maximum plasma concentration; XR, extended-release. aFor the combined use of XR and IR it is assumed that the first IR dose is taken at the time where both Tmax values are expected to coincide, providing a maximum peak of exposure. bIn BID regimen, AUC0-24 = 2*AUC0-12

In CHAPTER-1, bradykinin B2 receptor antagonist icatibant as on-demand treatment of breakthrough attacks while on prophylactic treatment with deucrictibant still showed evidence of efficacy, since mean breakthrough attack duration was comparable for the placebo-icatibant (1.12 days, n=25) and the deucrictibant-icatibant (1.05 days, n=20) groups.

This presentation includes data for an investigational product not yet approved by regulatory authorities.

Nonclinical NOAEL

Deucrictibant plasma concentration (ng/mL)

AUC ng·h/mL

Cmax ng/mL

Total dose (mg)

Human Cmax (ng/mL)c

267

281

327

Species

NOAEL Cmax (ng/mL)

Safety margins to nonclinical NOAEL, as unbound exposure

Mouse

4000

Rat

2000

9.8

9.3

8.0

Rabbit

1500

9.4

8.9

7.7

Monkey

3250

Total dose (mg)

Human AUC0-24h (ng·h/mL)c

1151

1620

1923

2683

Nonclinical assessment

Species

NOAEL AUC

(ng·h/mL)

Clinical safety margins to nonclinical NOAEL, as unbound exposure

Chronic toxicityd

Rat

7570

8.4

5.9

5.0

3.6

Monkey

15000

7.9

Embryo fetal development

Rat

14900

9.8

7.1

Rabbit

7870

9.1

7.6

5.5

Carcinogenicityd

Rat

11800

9.3

7.8

5.6

Mouse

5520

4.7

3.3

2.8

2.0

COI: A.L.: employee of GrayMatters Consulting and consultant to Pharvaris, holds stocks/stock options in Pharvaris, advisor to Kosa Pharma; J.B., Z-Y.Z., P.L., and N.C.: employees of Pharvaris, hold stocks/stock options in Pharvaris; M.R.: employee of CTI and consultant to Pharvaris.

Acfinowledgments: Medical writing services were provided by Daniel East, PhD, CMPP, of Envision Spark, an Envision Medical Communications agency, a part of Envision Pharma Group and funded by Pharvaris Netherlands B. V.

This study was sponsored by Pharvaris

COI: A.L.: employee of GrayMatters Consulting and consultant to Pharvaris, holds stocks/stock options in Pharvaris, advisor to Kosa Pharma;

J.B., Z-Y.Z., P.L., and N.C.: employees of Pharvaris, hold stocks/stock options in Pharvaris; M.R.: employee of CTI and consultant to Pharvaris.

This study was sponsored by Pharvaris

Deucrictibant: an investigational, selective, orally administered bradykinin B2 receptor antagonist under development for prophylactic (extended-release [XR] tablet) and on-demand (immediate-release [IR] capsule) treatment of

AE-BK attacks.6-18

Combined use: of deucrictibant XR tablet and deucrictibant IR capsule may occur in the real-world setting, subject to regulatory approval of each formulation, if deucrictibant IR capsule is used in the event of an attack occurring during prophylactic treatment with XR tablet.

1. Busse PJ, et al. N Engl J Med. 2020;382:1136-48. 2. Banerji A, et al. Ann Allergy Asthma Immunol. 2020;124:600-7. 3. Betschel SD, et al. J Allergy Clin Immunol Pract. 2023;11:2315-25. 4. Maurer M, et al. Allergy. 2022;77:1961-90. 5. Reshef A, et al. J Allergy Clin Immunol. 2024;154(2):398-411. 6. Lesage A, et al. Front Pharmacol. 2020;11:916. 7. Lesage A, et al. Int Immunopharmacol. 2022;105:108523. 8. RAPIDe-1. https://www.clinicaltrials.gov/study/NCT04618211. Accessed March 12, 2026. tı. Maurer M, et al. Lancet Haem. 2026; DOI: 10.1016/S2352-3026(25)00341-2. 10. RAPIDe-2. https://www.clinicaltrials.gov/study/NCT05396105. Accessed March 12, 2026. 11. RAPIDe-3. https://clinicaltrials.gov/study/NCT06343779. Accessed March 12, 2026. 12. Maurer M, et al. Presented at: AAAAI; February 24-27, 2023; San Antonio, TX, USA. 13. CHAPTER-1. https://www.clinicaltrials.gov/study/NCT05047185. Accessed March 12, 2026. 14. Aygören-Pürsün E, et al. Lancet Haem. 2026; DOI: 10.1016/S2352-3026(26)00004-9. 15. CHAPTER-3. https://clinicaltrials.gov/study/NCT06669754. Accessed March 12, 2026. 16. CHAPTER-4. https://clinicaltrials.gov/study/NCT06679881. Accessed March 12, 2026. 17. Aygören-Pürsün, et al. Presented at: EAACI; May 31-June 3, 2024; Valencia, Spain. 18. CREAATE. https://clinicaltrials.gov/study/NCT07266805. Accessed March 12, 2026.

Scenarios assumed that the first IR capsule was taken by 6 hours after the XR tablet, such that the peak plasma concentrations (Cmax) for the XR tablet and IR capsule would be reached at the same time, providing a maximum peak of exposure.

Total dose

(mg)

Total Cmax

(ng/mL)

Total AUC0-24h

(ng·h/mL)

XR + 1 IRa

281

1923

XR + 1 IR + 1 IRa

327

2683

AE-BK, bradykinin-mediated angioedema; AUC0-24h, area under the plasma concentration-time curve from time zero to 24 hours; Cmax, peak plasma concentration; h, hours; IR, immediate-release; Tmax, time to maximum plasma concentration; XR, extended-release. aFor the combined use of XR and IR it is assumed that the first IR dose is taken at the time where both Tmax values are expected to coincide, providing a maximum peak of exposure.

Plasma concentration-time profiles for evaluated combined use scenarios are presented in Figure 1B.

A B

XR (40 mga)

IR (2 x 20 mga) EC85

450

Deucrictibant plasma concentration (ng/mL)

400

350

300

250

200

150

100

0 4 8 12 16 20 24

Time (hours)

450

400

350

300

250

200

150

100

XR + 1 IR (60 mgb)

XR + 2 IR (80 mgb) EC85

0 4 8 12 16 20 24

Time (hours)

In the scenario where 1 IR capsule is taken in addition to 1 XR tablet (XR + 1 IR):

The anticipated human Cmax (281 ng/mL) would result in a margin of 8.9- to 19-fold the nonclinical Cmax at the NOAEL in different species (Table 2, Figure 2A).

In the scenario where a second IR capsule is administered 4 hours after the first IR capsule in addition to 1 XR tablet (XR + 2 IR):

The margin for the estimated human Cmax of 327 ng/mL is maintained between 7.7- and 16-fold the nonclinical Cmax at the NOAEL in different species (Table 2, Figure 2A).

The human AUC0-24h is estimated to be 2683 ng·h/mL with a margin of 2- to 7.9-fold the AUC at the NOAEL in different species (Table 3, Figure 2B).

XR + 1 IR + 1 IR

after 4hb

2 IRa

XR + 1 IRb

Total dose (mg)

Human Cmax (ng/mL)c

267

281

327

Species

NOAEL Cmax (ng/mL)

Safety margins to nonclinical NOAEL, as unbound exposure

Mouse

4000

Rat

2000

9.8

9.3

8.0

Rabbit

1500

9.4

8.9

7.7

Monkey

3250

Max nonclinical NOAEL

4000

59x

Max human Cmax (50 mg BID)

1 XR

2 IR

XR + 1 IR

XR + 2 IR

EC85(13.8 ng/mL)

14x

16x

17x

Monfiey NOAEL

3500

3000

Cmax ng/mL

2500

2000

1500

1000

500

1xIR 2xIR 3xIR 4xIR

7.9x

18x

Max human AUC0-24h (50 mg BID)

Max nonclinical NOAEL

Monfiey NOAEL

13x

11x

16000

14000

12000

AUC ng·h/mL

10000

8000

6000

4000

2000

1xIR 2xIR 3xIR 2h inter 4xIR 2h inter

1 XR

2 IR

XR + 1 IR

XR + 2 IR

XR + 1 IRb

XR + 1 IR +

1 IRb

2 IRa

Total dose (mg)

Human AUC0-24h (ng·h/mL)c

1151

1620

1923

2683

Nonclinical assessment

Species

NOAEL AUC

(ng·h/mL)

Clinical safety margins to nonclinical NOAEL, as unbound exposure

Chronic toxicityd

Rat

7570

8.4

5.9

5.0

3.6

Monkey

15000

7.9

Embryo fetal development

Rat

14900

9.8

7.1

Rabbit

7870

9.1

7.6

5.5

Carcinogenicityd

Rat

11800

9.3

7.8

5.6

Mouse

5520

4.7

3.3

2.8

2.0

AE-BK, bradykinin-mediated angioedema; AUC, area under the plasma concentration-time curve from time zero to 24 hours or the last measured concentration; IR, immediate-release; NOAEL, no observed adverse effect

In both combined scenarios, the estimated systemic exposure remains below the highest exposure explored in humans following clinical administration of deucrictibant 100 mg (as 50 mg BID) (Table 4, Figure 2A and B), a dose that was not associated with adverse reactions.

Exposure

Clinical study

Combination of

deucrictibant XR with IRa

Safety margina

Deucrictibant 50 mg BID

XR + 1 IR

XR + 1 IR + 1 IR

XR + 1 IR

XR + 1 IR + 1 IR

Cmax (ng/mL)

693

281

327

2.5

2.1

AUC0-24h (ng·h/mL)

9716b

1923

2683

5.1

3.6

The combined use of deucrictibant extended-release (XR) 40 mg tablet and immediate-release (IR) 20 mg capsule(s) in the event of an attack occurring during prophylactic treatment with XR tablet is

40 mg

≥7.7-fold

20 mg

40 mg

≥2.0-fold

20 mg

AUC0-24h

20 mg

Cmax

Remains below the highest dose

explored in human trials (100 mg, without adverse reactions)

20 mg

≥2.8-fold

40 mg

20 mg

≥8.tı-fold

40 mg

Safety margins

Systemic exposure

supported by adequate safety margins, subject to approval of each formulation by regulatory authorities.

Nonclinical NOAEL

representation of the deucrictibant XR tablet or IR capsule. 11

Disclaimer

Pharvaris NV published this content on April 16, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 16, 2026 at 21:21 UTC.