Zura Bio : Phase 1 Clinical Trial Evaluating the Pharmacokinetics and Pharmacodynamics of a Novel IL-17A and BAFF Dual Antagonist in Sjogren’s Syndrome

Binds to BAFF trimer and BAFF 60-merpreventing binding to

BAFF-R,TACI, and BCMA

BAFF

Phase 1 Clinical Trial Evaluating the Pharmacokinetics and Pharmacodynamics of a Novel IL-17A	#0373
and BAFF Dual Antagonist in Sjogren's Syndrome

Michael Howell,1 Kiran Nistala,1 Parisa Faghihi,1 Abid Sattar,2 Someit Sidhu3

1Zura Bio; 2Consultant to Zura Bio; 3Formerly at Zura Bio

Targeting IL-17A and BAFF

• Sjogren's syndrome is a systemic autoimmune disease

	Pharmacokinetics and Pharmacodynamics of Tibulizumab
Study Design	Target Engagement

characterized by progressive inflammation of the glands, largely

due to increased levels of activated lymphocytes (T and B cells)

and autoantibodies.

• Tibulizumab (ZB-106) is an IgG-scFv engineered by the fusion of

elements from TALTZ® (ixekizumab) and tabalumab that targets IL-17A and B cell activating factor (BAFF).

IL-17

Binds to IL-17A preventing IL-

17A/A and IL-17A/F heterodimerization

Anti-BAFF

D1

D113

D197

Cohort 1 (30mg SC)

Q4W Dosing

12 Week Follow-Up

D1

D113

D197

Cohort 2 (100mg SC)

Q4W Dosing

12 Week Follow-Up

D1

D113

D197

Cohort 3 (300mg SC)

Q4W Dosing

12 Week Follow-Up

IL-17A

Figure 2. Serological levels of total BAFF and IL-17A increased following tibulizumab administration, reflecting target engagement. At doses of 100 mg Q4W and higher, the total BAFF and IL-17A concentrations appear to plateau, suggesting near maximum target engagement has occurred.

Placebo

30mg Q4W

100mg Q4W

300mg Q4W

300mg Q2W

Anti-IL-17A

	D1	D113	D197
Cohort 4 (300mg SC)		Q2W Dosing			12 Week Follow-Up

SC dose administration

Phenotypic Analysis

Figure 3. Total B cell counts were dose-dependently reduced in Sjogren's syndrome patients throughout the clinical trial. Additionally, treatment with tibulizumab was associated with lower levels of of Th1 cells throughout the clinical trial.

Anti-BAFF

Study Objective

This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered tibulizumab in Sjogren's syndrome.

Methods

Patients

•	Male and female volunteers between the ages of 18 to 65.
•	Confirmed diagnosis of Sjogren's syndrome using the American-

Abbreviations: D = Day; Q2W = once every 2 weeks; Q4W = once every 4 weeks; SC = Subcutaneous

Baseline Characteristics

		30mg	100mg	300mg	300mg
	Placebo	Q4W	Q4W	Q4W	Q2W
Subjects	4	5	5	5	6
Female	3	5	4	5	6
Male	1	0	1	0	0
Race
White	3	5	4	5	6
Non-White	1	0	1	0	0
Age (years)
Mean	55.7	53.8	53.8	51.8	53.8

Total B Cells

Baseline	50
25
0
from
-25
% Change
-50
-75
	0	50	100	150	200

Visit Day

Placebo

30mg Q4W

100mg Q4W

300mg Q4W

300mg Q2W

% Change from Baseline

Th1 Cells

150

100

50

0
-50
0	50	100	150	200

Visit Day

	European Consensus Group criteria with active disease.
•	Seropositive for anti-nuclear antibodies (SSA or SSB) antibodies at

screening or documented within 6 months prior to screening.

Pharmacokinetic Assessment

• Human serum samples were analyzed for levels of tibulizumab using validated IL-17A and BAFF antigen capture ELISAs.

Target Engagement Assessment

• Levels of IL-17A and BAFF were assessed in human sera using

electrochemiluminescent assays.

Pharmacodynamic Assessment

• Epiontis ID® was used to phenotype cells using cell-type specific epigenetic markers.
• OLINK® was used to assess circulating levels of inflammatory mediators.

Statistical Analysis

• Statistical differences between treatment arms were assessed using Graph Pad Prism software.

© 2024 Zura Bio

Standard Error	10.4	9.4	8.1	6.5	13.3
Range (Min, Max)	(41.0, 63.0)	(41.0, 65.0)	(40.0, 61.0)	(42.0, 59.0)	(36.0, 65.0)
SS Antibody Status
SSA Positive	4/4	5/5	5/5	3/5	6/6
SSB Positive	4/4	2/5	0/5	2/5	3/6

Pharmacokinetics

Figure 1. Tibulizumab drug exposure was assessed using BAFF (Upper Panel) and IL-

17A (Lower Panel)

capture ELISAs. The observed and model- predicted PK profile is outlined in the figure. Based on the PK modeling, the T1/2 was calculated at 26.9 days.

Abbreviations: Q2W = once every 2 weeks; Q4W = once every 4 weeks

Table 1. The levels of 40 inflammatory mediators were analyzed using proteomic methods and presented as the percent change from baseline. The table below highlights some of the modulatory activity of tibulizumab on mediators associated with immune defense (serum amyloid a), Th2 biology (interleukin-5), T regulatory cells (interleukin-10) and fibroblast repair (basic fibroblast growth factor).

					30mg	100mg	300mg	300mg
	Placebo	Q4W	Q4W	Q4W	Q2W
Serum Amyloid A	0.66		33.40%	5.62		7.47%	-3.39		0.00%	-13.60		7.94%	-0.30		6.46%
	52.64±				±			±				±30.76%		±
Interleukin-5		35.33%	65.46	34.71%	-30.81	21.17%	-41.95		-42.78	15.31%
		±				±		-93.27±				±			±
Interleukin-10	24.60		122.5%	87.49	99.56%	6.35%	6742		4011%	6177	2287%
		±			±			±			±			±
Basic Fibroblast Growth Factor	-0.95	8.16%	-1.48	30.92%	43.32		334.9	92.18%	-55.72	20.33%
±		±	±69.71%	±	±

Conclusions

• Treatment with tibulizumab was well tolerated in patients with Sjogren's syndrome.
• Mechanistic reductions in total B cells and modulation of inflammatory mediators suggest the potential for tibulizumab in additional autoimmune conditions.

Acknowledgements

The authors thank the patients who volunteered to participate in the clinical trial and Emad Samani for bioinformatic support. This clinical trial was funded by Eli Lilly and Company.